BioPAX pathway converted from "Gene expression (Transcription)" in the Reactome database. Gene expression (Transcription) Gene expression (Transcription) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> RNA Polymerase II Transcription RNA Polymerase II Transcription This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Generic Transcription Pathway Generic Transcription Pathway This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Transcriptional Regulation by TP53 Transcriptional Regulation by TP53 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TP53 Regulates Metabolic Genes TP53 Regulates Metabolic Genes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 5.3.1.9 D-fructose 6-phosphate <=> alpha-D-Glucose 6-phosphate D-fructose 6-phosphate <=> alpha-D-Glucose 6-phosphate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29512 1 cytosol GO 0005829 beta-D-fructofuranose 6-phosphate(2-) [ChEBI:57634] beta-D-fructofuranose 6-phosphate(2-) 6-O-phosphonato-beta-D-fructofuranose beta-D-fructofuranose 6-phosphate dianion Reactome http://www.reactome.org ChEBI 57634 Reactome DB_ID: 30537 1 alpha-D-glucose 6-phosphate(2-) [ChEBI:58225] alpha-D-glucose 6-phosphate(2-) alpha-D-glucose 6-phosphate dianion alpha-D-glucopyranose 6-phosphate 6-O-phosphonato-alpha-D-glucopyranose alpha-D-glucose 6-phosphate ChEBI 58225 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10781970 GPI dimer [cytosol] GPI dimer Reactome DB_ID: 10781968 2 UniProt:Q8ILA4 Plasmodium falciparum NCBI Taxonomy 5833 UniProt Q8ILA4 Chain Coordinates 2 EQUAL 558 EQUAL Reactome Database ID Release 78 10781970 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10781970 Reactome R-PFA-70469 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-70469.1 GO 0004347 GO molecular function Reactome Database ID Release 78 10781971 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10781971 Reactome Database ID Release 78 10781975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10781975 Reactome R-PFA-70475 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-70475.1 The reversible isomerization of fructose-6-phosphate to form glucose-6-phosphate is catalyzed by cytosolic phosphoglucose isomerase (Noltman 1972; Xu and Beutler 1994; Tsuboi et al. 1958). 0121227022 ISBN 1972 Aldose-ketose isomerases Noltmann, EA The Enzymes, 3rd ed (Book): 271-354 7989588 Pubmed 1994 The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia Xu, W Beutler, Ernest J Clin Invest 94:2326-9 13538944 Pubmed 1958 Enzymes of the human erythrocyte. IV. Phosphoglucose isomerase, purification and properties. Tsuboi, KK Estrada, J Hudson, PB J Biol Chem 231:19-29 inferred by electronic annotation IEA GO IEA 1.1.1.49 alpha-D-glucose 6-phosphate + NADP+ => D-glucono-1,5-lactone 6-phosphate + NADPH + H+ alpha-D-glucose 6-phosphate + NADP+ => D-glucono-1,5-lactone 6-phosphate + NADPH + H+ This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 30537 1 Reactome DB_ID: 29366 1 NADP(3-) [ChEBI:58349] NADP(3-) NADP(+) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP trianion ChEBI 58349 Reactome DB_ID: 70106 1 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 31467 1 6-O-phosphono-D-glucono-1,5-lactone [ChEBI:16938] 6-O-phosphono-D-glucono-1,5-lactone ChEBI 16938 Reactome DB_ID: 29364 1 NADPH(4-) [ChEBI:57783] NADPH(4-) NADPH 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH tetraanion ChEBI 57783 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10781918 G6PD dimer and tetramer [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004345 GO molecular function Reactome Database ID Release 78 10781919 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10781919 Reactome Database ID Release 78 10781921 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10781921 Reactome R-PFA-70377 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-70377.1 Cytosolic glucose-6-phosphate dehydrogenase (G6PD) catalyzes the reaction of glucose 6-phosphate and NADP+ to form D-glucono-1,5-lactone 6-phosphate and NADPH + H+. This constitutes the first committed step of the pentose phosphate pathway and it is critical to the maintenance of NAPDH pool and redox homeostasis. For this reason, anti-cancer therapies are making this step as a prominent target in cancer therapy (Zhang et al. 2014). The reaction is inhibited by high ADP/AMP concentration, and by high NAPDH concentration. Biochemical studies indicate that both G6PD dimers and tetramers are catalytically active and present under physiological conditions in vivo (Au et al. 2000). Mutations that reduce the catalytic efficiency of G6PD are remarkably common in human populations; these appear to have a protective effect against malaria (e.g., Luzzatto and Afolayan 1968). 24066844 Pubmed 2014 Glucose-6-phosphate dehydrogenase: a biomarker and potential therapeutic target for cancer Zhang, Chunhua Zhang, Zheng Zhu, Yuechun Qin, Suofu Anticancer Agents Med Chem 14:280-9 10745013 Pubmed 2000 Human glucose-6-phosphate dehydrogenase: the crystal structure reveals a structural NADP(+) molecule and provides insights into enzyme deficiency Au, SW Gover, S Lam, VM Adams, MJ Structure 8:293-303 5666113 Pubmed 1968 Enzymic properties of different types of human erythrocyte glucose-6-phosphate dehydrogenase, with characterization of two new genetic variants Luzzatto, L Afolayan, A J Clin Invest 47:1833-42 inferred by electronic annotation IEA GO IEA 1.8.1.9 thioredoxin, oxidized + NADPH + H+ => thioredoxin, reduced + NADP+ thioredoxin, oxidized + NADPH + H+ => thioredoxin, reduced + NADP+ regeneration of active (reduced) Thioredoxin This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 70106 1 Reactome DB_ID: 10783107 1 UniProt:Q4VWQ3 trx3 UniProt Q4VWQ3 Intra-chain Crosslink via L-cystine (cross-link) at 32 and 35 (in Homo sapiens) 32 EQUAL L-cystine (cross-link) 2 EQUAL 105 EQUAL Reactome DB_ID: 29364 1 Reactome DB_ID: 10783109 1 2 EQUAL 105 EQUAL Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10783128 TNXRD1:FAD dimer [cytosol] TNXRD1:FAD dimer Reactome DB_ID: 29386 2 FAD [ChEBI:16238] FAD Flavin adenine dinucleotide ChEBI 16238 Converted from EntitySet in Reactome Reactome DB_ID: 10783126 2 Homologues of TXNRD1 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TXNRD1 [cytosol] GR3 [cytosol] trxr2 [cytosol] UniProt A0A144A3W0 UniProt O15770 UniProt P61076 Reactome Database ID Release 78 10783128 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783128 Reactome R-PFA-73532 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-73532.1 GO 0004791 GO molecular function Reactome Database ID Release 78 10783129 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783129 Reactome Database ID Release 78 10783131 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783131 Reactome R-PFA-73646 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-73646.1 Cytosolic thioredoxin reductase catalyzes the reaction of thioredoxin, oxidized and NADPH + H+ to form thioredoxin, reduced and NADP+ (Urig et al. 2006). 16750198 Pubmed 2006 Truncated mutants of human thioredoxin reductase 1 do not exhibit glutathione reductase activity Urig, S Lieske, J Fritz-Wolf, K Irmler, A Becker, K FEBS Lett 580:3595-600 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10796828 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796828 Reactome R-PFA-5628897 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-5628897.1 While the p53 tumor suppressor protein (TP53) is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism to prevent tumor development. TP53 regulates transcription of many genes involved in the metabolism of carbohydrates, nucleotides and amino acids, protein synthesis and aerobic respiration.<p>TP53 stimulates transcription of TIGAR, a D-fructose 2,6-bisphosphatase. TIGAR activity decreases glycolytic rate and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006). TP53 may also negatively regulate the rate of glycolysis by inhibiting the expression of glucose transporters GLUT1, GLUT3 and GLUT4 (Kondoh et al. 2005, Schwartzenberg-Bar-Yoseph et al. 2004, Kawauchi et al. 2008).<p>TP53 negatively regulates several key points in PI3K/AKT signaling and downstream mTOR signaling, decreasing the rate of protein synthesis and, hence, cellular growth. TP53 directly stimulates transcription of the tumor suppressor PTEN, which acts to inhibit PI3K-mediated activation of AKT (Stambolic et al. 2001). TP53 stimulates transcription of sestrin genes, SESN1, SESN2, and SESN3 (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007). One of sestrin functions may be to reduce and reactivate overoxidized peroxiredoxin PRDX1, thereby reducing ROS levels (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009). Another function of sestrins is to bind the activated AMPK complex and protect it from AKT-mediated inactivation. By enhancing AMPK activity, sestrins negatively regulate mTOR signaling (Budanov and Karin 2008, Cam et al. 2014). The expression of DDIT4 (REDD1), another negative regulator of mTOR signaling, is directly stimulated by TP63 and TP53. DDIT4 prevents AKT-mediated inactivation of TSC1:TSC2 complex, thus inhibiting mTOR cascade (Cam et al. 2014, Ellisen et al. 2002, DeYoung et al. 2008). TP53 may also be involved, directly or indirectly, in regulation of expression of other participants of PI3K/AKT/mTOR signaling, such as PIK3CA (Singh et al. 2002), TSC2 and AMPKB (Feng et al. 2007). <p>TP53 regulates mitochondrial metabolism through several routes. TP53 stimulates transcription of SCO2 gene, which encodes a mitochondrial cytochrome c oxidase assembly protein (Matoba et al. 2006). TP53 stimulates transcription of RRM2B gene, which encodes a subunit of the ribonucleotide reductase complex, responsible for the conversion of ribonucleotides to deoxyribonucleotides and essential for the maintenance of mitochondrial DNA content in the cell (Tanaka et al. 2000, Bourdon et al. 2007, Kulawiec et al. 2009). TP53 also transactivates mitochondrial transcription factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance (Park et al. 2009). Finally, TP53 stimulates transcription of the mitochondrial glutaminase GLS2, leading to increased mitochondrial respiration rate and reduced ROS levels (Hu et al. 2010). <p>The great majority of tumor cells generate energy through aerobic glycolysis, rather than the much more efficient aerobic mitochondrial respiration, and this metabolic change is known as the Warburg effect (Warburg 1956). Since the majority of tumor cells have impaired TP53 function, and TP53 regulates a number of genes involved in glycolysis and mitochondrial respiration, it is likely that TP53 inactivation plays an important role in the metabolic derangement of cancer cells such as the Warburg effect and the concomitant increased tumorigenicity (reviewed by Feng and Levine 2010). On the other hand, some mutations of TP53 in Li-Fraumeni syndrome may result in the retention of its wild-type metabolic activities while losing cell cycle and apoptosis functions (Wang et al. 2013). Consistent with such human data, some mutations of p53, unlike p53 null state, retain the ability to regulate energy metabolism while being inactive in regulating its classic gene targets involved in cell cycle, apoptosis and senescence. Retention of metabolic and antioxidant functions of p53 protects p53 mutant mice from early onset tumorigenesis (Li et al. 2012). 18344994 Pubmed 2008 Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses Papadia, Sofia Soriano, Francesc X Léveillé, Frédéric Martel, Marc-Andre Dakin, Kelly A Hansen, Henrik H Kaindl, Angela Sifringer, Marco Fowler, Jill Stefovska, Vanya McKenzie, Grahame Craigon, Marie Corriveau, Roderick Ghazal, Peter Horsburgh, Karen Yankner, Bruce A Wyllie, David J A Ikonomidou, Chrysanthy Hardingham, Giles E Nat. Neurosci. 11:476-87 18391940 Pubmed 2008 p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation Kawauchi, Keiko Araki, Keigo Tobiume, Kei Tanaka, Nobuyuki Nat. Cell Biol. 10:611-8 13298683 Pubmed 1956 On the origin of cancer cells WARBURG, O Science 123:309-14 20399660 Pubmed 2010 The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein Feng, Zhaohui Levine, Arnold J Trends Cell Biol. 20:427-34 15665293 Pubmed 2005 Glycolytic enzymes can modulate cellular life span Kondoh, Hiroshi Lleonart, Matilde E Gil, Jesús Wang, Jing Degan, Paolo Peters, Gordon Martinez, Dolores Carnero, Amancio Beach, David Cancer Res. 65:177-85 16728594 Pubmed 2006 p53 regulates mitochondrial respiration Matoba, Satoaki Kang, Ju-Gyeong Patino, Willmar D Wragg, Andrew Boehm, Manfred Gavrilova, Oksana Hurley, Paula J Bunz, Fred Hwang, Paul M Science 312:1650-3 17409411 Pubmed 2007 The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways Feng, Zhaohui Hu, Wenwei de Stanchina, E Teresky, Angelika K Jin, Shengkan Lowe, S Levine, Arnold J Cancer Res. 67:3043-53 12453409 Pubmed 2002 REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species Ellisen, Leif W Ramsayer, Kate D Johannessen, Cory M Yang, Annie Beppu, Hideyuki Minda, Karolina Oliner, Jonathan D McKeon, Frank Haber, Daniel A Mol. Cell 10:995-1005 9926927 Pubmed 1999 PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes Velasco-Miguel, S Buckbinder, L Jean, P Gelbert, L Talbott, R Laidlaw, J Seizinger, B Kley, N Oncogene 18:127-37 17540029 Pubmed 2007 NGF-mediated transcriptional targets of p53 in PC12 neuronal differentiation Brynczka, Christopher Labhart, Paul Merrick, B Alex BMC Genomics 8:139 11959846 Pubmed 2002 p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas Singh, B Reddy, Pabbathi G Goberdhan, Andy Walsh, Christine Dao, Su Ngai, Ivan Chou, Ting Chao O-Charoenrat, Pornchai Levine, Arnold J Rao, Pulivarthi H Stoffel, Archontoula Genes Dev. 16:984-93 18198340 Pubmed 2008 Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling DeYoung, Maurice Phillip Horak, Peter Sofer, Avi Sgroi, Dennis Ellisen, Leif W Genes Dev. 22:239-51 15059920 Pubmed 2004 The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression Schwartzenberg-Bar-Yoseph, Fabiana Armoni, Michal Karnieli, Eddy Cancer Res. 64:2627-33 20378837 Pubmed 2010 Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function Hu, Wenwei Zhang, Cen Wu, Rui Sun, Yvonne Levine, Arnold Feng, Zhaohui Proc. Natl. Acad. Sci. U.S.A. 107:7455-60 19439913 Pubmed 2009 p53 regulates mtDNA copy number and mitocheckpoint pathway Kulawiec, Mariola Ayyasamy, Vanniarajan Singh, Keshav K J Carcinog 8:8 22682249 Pubmed 2012 Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence Li, Tongyuan Kon, Ning Jiang, Le Tan, Minjia Ludwig, Thomas Zhao, Yingming Baer, Richard J Gu, Wei Cell 149:1269-83 22864287 Pubmed 2012 PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53 Cui, Gaofeng Park, Sungman Badeaux, Aimee I Kim, Donghwa Lee, Joseph Thompson, James R Yan, Fei Kaneko, Satoshi Yuan, Zengqiang Botuyan, Maria Victoria Bedford, Mark T Cheng, Jin Q Mer, Georges Nat. Struct. Mol. Biol. 19:916-24 18692468 Pubmed 2008 p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling Budanov, Andrei V Karin, M Cell 134:451-60 19696408 Pubmed 2009 p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content Park, Joon-Young Wang, Ping-yuan Matsumoto, Takumi Sung, Ho Joong Ma, Wenzhe Choi, Jeong W Anderson, Stasia A Leary, Scot C Balaban, Robert S Kang, Ju-Gyeong Hwang, Paul M Circ. Res. 105:705-12, 11 p following 712 12203114 Pubmed 2002 Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability Budanov, Andrei V Shoshani, Tzipora Faerman, Alexander Zelin, Elena Kamer, Iris Kalinski, Hagar Gorodin, Svetlana Fishman, Alla Chajut, Ayelet Einat, Paz Skaliter, Rami Gudkov, Andrei V Chumakov, Peter M Feinstein, Elena Oncogene 21:6017-31 16839880 Pubmed 2006 TIGAR, a p53-inducible regulator of glycolysis and apoptosis Bensaad, Karim Tsuruta, Atsushi Selak, Mary A Vidal, M Nieves Calvo Nakano, Katsunori Bartrons, Ramon Gottlieb, Eyal Vousden, Karen H Cell 126:107-20 23484829 Pubmed 2013 Increased oxidative metabolism in the Li-Fraumeni syndrome Wang, Ping-yuan Ma, Wenzhe Park, Joon-Young Celi, Francesco S Arena, Ross Choi, Jeong W Ali, Qais A Tripodi, Dotti J Zhuang, Jie Lago, Cory U Strong, Louise C Talagala, S Lalith Balaban, Robert S Kang, Ju-Gyeong Hwang, Paul M N. Engl. J. Med. 368:1027-32 24366874 Pubmed 2014 p53/TAp63 and AKT regulate mammalian target of rapamycin complex 1 (mTORC1) signaling through two independent parallel pathways in the presence of DNA damage Cam, Maren Bid, Hemant K Xiao, Linlin Zambetti, Gerard P Houghton, Peter J Cam, Hakan J. Biol. Chem. 289:4083-94 15105503 Pubmed 2004 Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD Budanov, Andrei V Sablina, Anna A Feinstein, Elena Koonin, Eugene V Chumakov, Peter M Science 304:596-600 19822145 Pubmed 2009 Role of sestrin2 in peroxide signaling in macrophages Essler, Silke Dehne, Nathalie Brüne, Bernhard FEBS Lett. 583:3531-5 10716435 Pubmed 2000 A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage Tanaka, Hiroshi Arakawa, Hirofumi Yamaguchi, Tatsuya Shiraishi, Kenji Fukuda, Seisuke Matsui, Kuniko Takei, Yoshiki Nakamura, Yusuke Nature 404:42-49 11545734 Pubmed 2001 Regulation of PTEN transcription by p53 Stambolic, V MacPherson, D Sas, D Lin, Y Snow, B Jang, Y Benchimol, S Mak, T W Mol. Cell 8:317-25 17486094 Pubmed 2007 Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion Bourdon, Alice Minai, Limor Serre, Valérie Jais, Jean-Philippe Sarzi, Emmanuelle Aubert, Sophie Chrétien, Dominique de Lonlay, Pascale Paquis-Flucklinger, Veronique Arakawa, Hirofumi Nakamura, Yusuke Munnich, A Rötig, Agnès Nat. Genet. 39:776-80 inferred by electronic annotation IEA GO IEA TP53 Regulates Transcription of Cell Death Genes TP53 Regulates Transcription of Cell Death Genes This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TP53 Regulates Transcription of Genes Involved in Cytochrome C Release TP53 Regulates Transcription of Genes Involved in Cytochrome C Release This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TRIAP1 binds PRELID1, PRELID3A TRIAP1 binds PRELID1, PRELID3A This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10794026 1 mitochondrial intermembrane space GO 0005758 UniProt:Q8I227 UniProt Q8I227 1 EQUAL 76 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10794035 1 PRELID1, PRELID3A [mitochondrial intermembrane space] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PRELID1 [mitochondrial intermembrane space] UniProt Q8IE73 Reactome DB_ID: 10794037 1 TRIAP1:PRELID1, PRELID3A [mitochondrial intermembrane space] TRIAP1:PRELID1, PRELID3A Reactome DB_ID: 10794026 1 1 EQUAL 76 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10794035 1 Reactome Database ID Release 78 10794037 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794037 Reactome R-PFA-6801235 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6801235.1 Reactome Database ID Release 78 10794039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794039 Reactome R-PFA-6801242 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6801242.1 In the mitochondrial intermembrane space, TP53-regulated inhibitor of apoptosis 1 (TRIAP1) forms a complex with mitochondrial PRELI domain-containing protein 1 (PRELID1, PRELI) (Potting et al. 2013). TRIAP1 is also proposed to form a complex with PRELI domain containing protein 3A (PRELID3A) (Miliara et al. 2015). 23931759 Pubmed 2013 TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid Potting, Christoph Tatsuta, Takashi König, Tim Haag, Mathias Wai, Timothy Aaltonen, Mari J Langer, Thomas Cell Metab. 18:287-95 26071602 Pubmed 2015 Structural insight into the TRIAP1/PRELI-like domain family of mitochondrial phospholipid transfer complexes Miliara, Xeni Garnett, James A Tatsuta, Takashi Abid Ali, Ferdos Baldie, Heather Pérez-Dorado, Inmaculada Simpson, Peter Yague, Ernesto Langer, Thomas Matthews, Stephen EMBO Rep. 16:824-35 inferred by electronic annotation IEA GO IEA TRIAP1:PRELID1, PRELID3A transports PA from the outer to the inner mitochondrial membrane TRIAP1:PRELID1, PRELID3A transports PA from the outer to the inner mitochondrial membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 1500590 1 mitochondrial outer membrane GO 0005741 phosphatidic acid [ChEBI:16337] phosphatidic acid ChEBI 16337 Reactome DB_ID: 1524101 1 mitochondrial inner membrane GO 0005743 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10794037 GO 0005319 GO molecular function Reactome Database ID Release 78 10794040 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794040 Reactome Database ID Release 78 10794042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794042 Reactome R-PFA-6801250 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6801250.1 The complex of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) and mitochondrial PRELI domain-containing protein 1 PRELID1 (TRIAP1:PRELID1) facilitates transport of phosphatidic acid (PA) from the outer mitochondrial membrane to the inner mitochondrial membrane. At the inner mitochondrial membrane, the PA is used for the synthesis of cardiolipin (CL). CL prevents the release of cytochrome C from mitochondria, thus playing an anti-apoptotic role (Potting et al. 2013). The complex between TRIAP1 and PRELI domain containing protein 3A (PRELID3A) is suggested to perform the same PA transport activity (Miliara et al. 2015) inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797822 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797822 Reactome R-PFA-6803204 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6803204.1 Apoptotic transcriptional targets of TP53 include genes that regulate the permeability of the mitochondrial membrane and/or cytochrome C release, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1 (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013), thus promoting the activation of the apoptotic pathway.<p>Transcriptional activation of TP53AIP1 requires phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). 12606722 Pubmed 2003 The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase Passer, Brent J Nancy-Portebois, Vanessa Amzallag, Nathalie Prieur, Sylvie Cans, Christophe Roborel de Climens, Aude Fiucci, Giusy Bouvard, Veronique Tuynder, Marcel Susini, Laurent Morchoisne, Stéphanie Crible, Virginie Lespagnol, Alexandra Dausset, Jean Oren, M Amson, Robert Telerman, Adam Proc. Natl. Acad. Sci. U.S.A. 100:2284-9 15273740 Pubmed 2004 AMID is a p53-inducible gene downregulated in tumors Wu, Min Xu, Liang-Guo Su, Tian Tian, Yang Zhai, Zhonghe Shu, Hong-Bing Oncogene 23:6815-9 10807576 Pubmed 2000 Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis Oda, E Ohki, R Murasawa, H Nemoto, J Shibue, T Yamashita, T Tokino, T Taniguchi, T Tanaka, N Science 288:1053-8 23365256 Pubmed 2013 ASPP1/2 regulate p53-dependent death of retinal ganglion cells through PUMA and Fas/CD95 activation in vivo Wilson, Ariel M Morquette, Barbara Abdouh, Mohamed Unsain, Nicolás Barker, Philip A Feinstein, Elena Bernier, Gilbert Di Polo, Adriana J. Neurosci. 33:2205-16 11463392 Pubmed 2001 PUMA, a novel proapoptotic gene, is induced by p53 Nakano, K Vousden, KH Mol Cell 7:683-94 11511362 Pubmed 2001 p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis Okamura, S Arakawa, H Tanaka, T Nakanishi, H Ng, C C Taya, Y Monden, M Nakamura, Y Mol. Cell 8:85-94 12402042 Pubmed 2002 BID regulation by p53 contributes to chemosensitivity Sax, Joanna K Fei, Peiwen Murphy, Maureen E Bernhard, Eric Korsmeyer, Stanley J El-Deiry, Wafik S Nat. Cell Biol. 4:842-9 15607964 Pubmed 2004 Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth Fei, Peiwen Wang, Wenge Kim, Seok-hyun Wang, Shulin Burns, Timothy F Sax, Joanna K Buzzai, Monica Dicker, David T McKenna, W Gillies Bernhard, Eric J El-Deiry, Wafik S Cancer Cell 6:597-609 14729977 Pubmed 2004 ASPP1 and ASPP2: common activators of p53 family members Bergamaschi, Daniele Samuels, Y Jin, B Duraisingham, Sai Crook, Tim Lu, Xin Mol. Cell. Biol. 24:1341-50 22766503 Pubmed 2012 iASPPsv antagonizes apoptosis induced by chemotherapeutic agents in MCF-7 cells and mouse thymocytes Wang, Lin Xing, Haiyan Tian, Zheng Peng, Leiwen Li, Y Tang, Kejing Rao, Qing Wang, Min Wang, Jianxiang Biochem. Biophys. Res. Commun. 424:414-20 15735003 Pubmed 2005 p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway Park, Woong-Ryeon Nakamura, Yusuke Cancer Res. 65:1197-206 11684014 Pubmed 2001 ASPP proteins specifically stimulate the apoptotic function of p53 Samuels-Lev, Y O'Connor, D J Bergamaschi, D Trigiante, G Hsieh, J K Zhong, S Campargue, I Naumovski, L Crook, T Lu, X Mol. Cell 8:781-94 15126337 Pubmed 2004 Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53 Li, CQ Robles, AI Hanigan, CL Hofseth, LJ Trudel, LJ Harris, CC Wogan, GN Cancer Res 64:3022-9 12851404 Pubmed 2003 TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity Tomasini, Richard Samir, Amina Azizi Carrier, Alice Isnardon, Daniel Cecchinelli, Barbara Soddu, Silvia Malissen, Bernard Dagorn, Jean-Charles Iovanna, Juan L Dusetti, Nelson J J. Biol. Chem. 278:37722-9 18676979 Pubmed 2008 Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax Patel, Seema George, Roger Autore, Flavia Fraternali, Franca Ladbury, JE Nikolova, Penka V Nucleic Acids Res. 36:5139-51 7834749 Pubmed 1995 Tumor suppressor p53 is a direct transcriptional activator of the human bax gene Miyashita, T Reed, J C Cell 80:293-9 inferred by electronic annotation IEA GO IEA TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> RABGGTA binds RABGGTB RABGGTA binds RABGGTB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10794012 1 plasma membrane GO 0005886 UniProt:Q8IL46 UniProt Q8IL46 1 EQUAL 567 EQUAL Reactome DB_ID: 10794017 1 UniProt:C6KSM5 UniProt C6KSM5 2 EQUAL 331 EQUAL Reactome DB_ID: 10794019 1 RGGT [plasma membrane] RGGT Reactome DB_ID: 10794012 1 1 EQUAL 567 EQUAL Reactome DB_ID: 10794017 1 2 EQUAL 331 EQUAL Reactome Database ID Release 78 10794019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794019 Reactome R-PFA-6801105 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6801105.1 Reactome Database ID Release 78 10794021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794021 Reactome R-PFA-6801101 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6801101.1 RABGGTA associates with RABGGTB to form RAB geranylgeranyl transferase (RGGT or RAB GGTase). This was initially shown using proteins purified from rat brain (Seabra et al. 1992), but the complex is evolutionarily conserved in human cells (Baron and Seabra 2008). 1321151 Pubmed 1992 Rab geranylgeranyl transferase. A multisubunit enzyme that prenylates GTP-binding proteins terminating in Cys-X-Cys or Cys-Cys Seabra, M C Goldstein, J L Sudhof, T C Brown, M S J. Biol. Chem. 267:14497-503 18532927 Pubmed 2008 Rab geranylgeranylation occurs preferentially via the pre-formed REP-RGGT complex and is regulated by geranylgeranyl pyrophosphate Baron, Rudi A Seabra, Miguel C Biochem. J. 415:67-75 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797818 Reactome R-PFA-6803205 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6803205.1 The exact mechanisms of action of several other pro-apoptotic TP53 (p53) targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP, remain uncertain (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012). 15577913 Pubmed 2004 The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells Phan, Ryan T Dalla-Favera, Riccardo Nature 432:635-9 17442733 Pubmed 2007 p53-dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion Zhang, Ai-Hong Rao, Jaladanki N Zou, Tongtong Liu, Lan Marasa, Bernard S Xiao, Lan Chen, Jie Turner, Douglas J Wang, Jian-Ying Am. J. Physiol., Cell Physiol. 293:C379-89 19549844 Pubmed 2009 BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma Saito, Masumichi Novak, Urban Piovan, Erich Basso, K Sumazin, Pavel Schneider, Christof Crespo, Marta Shen, Qiong Bhagat, G Califano, A Chadburn, Amy Pasqualucci, Laura Dalla-Favera, Riccardo Proc. Natl. Acad. Sci. U.S.A. 106:11294-9 16249378 Pubmed 2006 BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma Margalit, Ofer Amram, Hila Amariglio, Ninette Simon, Amos J Shaklai, Sigal Granot, Galit Minsky, Neri Shimoni, Avichai Harmelin, Alon Givol, David Shohat, Mordechai Oren, M Rechavi, Gideon Blood 107:1599-607 10733530 Pubmed 2000 PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family Attardi, L D Reczek, E E Cosmas, C Demicco, E G McCurrach, M E Lowe, S W Jacks, T Genes Dev. 14:704-18 16140933 Pubmed 2005 Identification of novel p53 target genes in ionizing radiation response Jen, Kuang-Yu Cheung, Vivian G Cancer Res. 65:7666-73 11054413 Pubmed 2001 Bcl-G, a novel pro-apoptotic member of the Bcl-2 family Guo, B Godzik, A Reed, J C J. Biol. Chem. 276:2780-5 11919562 Pubmed 2002 A polymorphic microsatellite that mediates induction of PIG3 by p53 Contente, Ana Dittmer, Alexandra Koch, Manuela C Roth, Judith Dobbelstein, Matthias Nat. Genet. 30:315-20 14614825 Pubmed 2003 Perp is a mediator of p53-dependent apoptosis in diverse cell types Ihrie, Rebecca A Reczek, Elizabeth Horner, Jennifer S Khachatrian, Leili Sage, J Jacks, Tyler Attardi, Laura D Curr. Biol. 13:1985-90 23059823 Pubmed 2012 Bcl-2 family member Bcl-G is not a proapoptotic protein Giam, M Okamoto, T Mintern, J D Strasser, A Bouillet, P Cell Death Dis 3:e404 19040420 Pubmed 2009 P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma Davies, Lyndsay Gray, Donna Spiller, Dave White, Mike R H Damato, Bertil Grierson, Ian Paraoan, Luminita J. Cell. Mol. Med. 13:1995-2007 15377670 Pubmed 2004 NDRG1 is necessary for p53-dependent apoptosis Stein, Susanne Thomas, Emily K Herzog, Birger Westfall, Matthew D Rocheleau, Jonathan V Jackson, Roger S Wang, Mai Liang, Peng J. Biol. Chem. 279:48930-40 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797820 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797820 Reactome R-PFA-5633008 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-5633008.1 GO 0042981 GO biological process The tumor suppressor TP53 (p53) exerts its tumor suppressive role in part by regulating transcription of a number of genes involved in cell death, mainly apoptotic cell death. The majority of apoptotic genes that are transcriptional targets of TP53 promote apoptosis, but there are also several TP53 target genes that inhibit apoptosis, providing cells with an opportunity to attempt to repair the damage and/or recover from stress. <br>Pro-apoptotic transcriptional targets of TP53 involve TRAIL death receptors TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2), as well as the FASL/CD95L death receptor FAS (CD95). TRAIL receptors and FAS induce pro-apoptotic signaling in response to external stimuli via extrinsic apoptosis pathway (Wu et al. 1997, Takimoto et al. 2000, Guan et al. 2001, Liu et al. 2004, Ruiz de Almodovar et al. 2004, Liu et al. 2005, Schilling et al. 2009, Wilson et al. 2013). IGFBP3 is a transcriptional target of TP53 that may serve as a ligand for a novel death receptor TMEM219 (Buckbinder et al. 1995, Ingermann et al. 2010).<p>TP53 regulates expression of a number of genes involved in the intrinsic apoptosis pathway, triggered by the cellular stress. Some of TP53 targets, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1, regulate the permeability of the mitochondrial membrane and/or cytochrome C release (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013). Other pro-apoptotic genes, either involved in the intrinsic apoptosis pathway, extrinsic apoptosis pathway or pyroptosis (inflammation-related cell death), which are transcriptionally regulated by TP53 are cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10 (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007).<p>It is uncertain how exactly some of the pro-apoptotic TP53 targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP contribute to apoptosis (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012).<p>TP53 is stabilized in response to cellular stress by phosphorylation on at least serine residues S15 and S20. Since TP53 stabilization precedes the activation of cell death genes, the TP53 tetramer phosphorylated at S15 and S20 is shown as a regulator of pro-apoptotic/pro-cell death genes. Some pro-apoptotic TP53 target genes, such as TP53AIP1, require additional phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). Additional post-translational modifications of TP53 may be involved in transcriptional regulation of genes presented in this pathway and this information will be included as evidence becomes available.<p>Activation of some pro-apoptotic TP53 targets, such as BAX, FAS, BBC3 (PUMA) and TP53I3 (PIG3) requires the presence of the complex of TP53 and an ASPP protein, either PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Samuels-Lev et al. 2001, Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013), indicating how the interaction with specific co-factors modulates the cellular response/outcome.<p>TP53 family members TP63 and or TP73 can also activate some of the pro-apoptotic TP53 targets, such as FAS, BAX, BBC3 (PUMA), TP53I3 (PIG3), CASP1 and PERP (Bergamaschi et al. 2004, Jain et al. 2005, Ihrie et al. 2005, Patel et al. 2008, Schilling et al. 2009, Celardo et al. 2013).<p> <br>For a review of the role of TP53 in apoptosis and pro-apoptotic transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015. 16230375 Pubmed 2005 Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity Liu, Xiangguo Yue, Ping Khuri, Fadlo R Sun, Shi-Yong Cancer Res. 65:9169-75 17349958 Pubmed 2007 DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage Taira, Naoe Nihira, Keishi Yamaguchi, Tomoko Miki, Yoshio Yoshida, Kiyotsugu Mol. Cell 25:725-38 9326928 Pubmed 1997 KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene Wu, G S Burns, T F McDonald, E R Jiang, W Meng, R Krantz, I D Kao, G Gan, D D Zhou, J Y Muschel, R Hamilton, S R Spinner, N B Markowitz, S Wu, G el-Deiry, WS Nat. Genet. 17:141-3 15580302 Pubmed 2005 Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis Sadasivam, S Gupta, S Radha, Vegesna Batta, Kiran Kundu, Tapas K Swarup, Ghanshyam Oncogene 24:627-36 24739573 Pubmed 2014 Unravelling mechanisms of p53-mediated tumour suppression Bieging, Kathryn T Mello, Stephano Spano Attardi, Laura D Nat. Rev. Cancer 14:359-70 18719709 Pubmed 2008 A complex barcode underlies the heterogeneous response of p53 to stress Murray-Zmijewski, Fiona Slee, Elizabeth A Lu, Xin Nat. Rev. Mol. Cell Biol. 9:702-12 23703390 Pubmed 2013 Caspase-1 is a novel target of p63 in tumor suppression Celardo, I Grespi, F Antonov, A Bernassola, F Garabadgiu, A V Melino, G Amelio, I Cell Death Dis 4:e645 17284521 Pubmed 2007 Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death Brough, D Rothwell, NJ J Cell Sci 120:772-81 14688482 Pubmed 2003 Caspase 10 levels are increased following DNA damage in a p53-dependent manner Rikhof, Bart Corn, Paul G El-Deiry, Wafik S Cancer Biol. Ther. 2:707-12 11559530 Pubmed 2001 APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis Robles, A I Bemmels, N A Foraker, A B Harris, C C Cancer Res. 61:6660-4 15797384 Pubmed 2005 Perp is a p63-regulated gene essential for epithelial integrity Ihrie, Rebecca A Marques, Michelle R Nguyen, Bichchau T Horner, Jennifer S Papazoglu, Cristian Bronson, Roderick T Mills, Alea A Attardi, Laura D Cell 120:843-56 15289308 Pubmed 2004 p53 upregulates death receptor 4 expression through an intronic p53 binding site Liu, Xiangguo Yue, Ping Khuri, Fadlo R Sun, Shi-Yong Cancer Res. 64:5078-83 20353938 Pubmed 2010 Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer Ingermann, Angela R Yang, Yong-Feng Han, Jinfeng Mikami, Aki Garza, Amanda E Mohanraj, Lathika Fan, Lingbo Idowu, Michael Ware, Joy L Kim, Ho-Seong Lee, Dae-Yeol Oh, Youngman J. Biol. Chem. 285:30233-46 14623878 Pubmed 2004 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) decoy receptor TRAIL-R3 is up-regulated by p53 in breast tumor cells through a mechanism involving an intronic p53-binding site Ruiz de Almodóvar, Carmen Ruiz-Ruiz, Carmen Rodríguez, Antonio Ortiz-Ferrón, Gustavo Redondo, Juan Miguel López-Rivas, Abelardo J. Biol. Chem. 279:4093-101 18431400 Pubmed 2008 Transcriptional control of human p53-regulated genes Riley, Todd Sontag, Eduardo Chen, Patricia Levine, Arnold Nat. Rev. Mol. Cell Biol. 9:402-12 10973264 Pubmed 2000 Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis Lin, Y Ma, W Benchimol, S Nat. Genet. 26:122-7 11382926 Pubmed 2001 Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene Guan, B Yue, P Clayman, G L Sun, S Y J. Cell. Physiol. 188:98-105 10777207 Pubmed 2000 Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site Takimoto, R el-Deiry, WS Oncogene 19:1735-43 7566179 Pubmed 1995 Induction of the growth inhibitor IGF-binding protein 3 by p53 Buckbinder, L Talbott, R Velasco-Miguel, S Takenaka, I Faha, B Seizinger, B R Kley, N Nature 377:646-9 19615968 Pubmed 2009 Active transcription of the human FAS/CD95/TNFRSF6 gene involves the p53 family Schilling, Tobias Schleithoff, Elisa Schulze Kairat, Astrid Melino, Gerry Stremmel, Wolfgang Oren, M Krammer, Peter H Müller, Martina Biochem. Biophys. Res. Commun. 387:399-404 16135520 Pubmed 2005 Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin Jain, Nishant Gupta, S Sudhakar, Ch Radha, Vegesna Swarup, Ghanshyam J. Biol. Chem. 280:36664-73 12089322 Pubmed 2002 Apoptotic threshold is lowered by p53 transactivation of caspase-6 MacLachlan, Timothy K El-Deiry, Wafik S Proc. Natl. Acad. Sci. U.S.A. 99:9492-7 26122615 Pubmed 2015 p53 in survival, death and metabolic health: a lifeguard with a licence to kill Kruiswijk, Flore Labuschagne, Christiaan F Vousden, Karen H Nat. Rev. Mol. Cell Biol. 16:393-405 11278253 Pubmed 2001 Direct transcriptional activation of human caspase-1 by tumor suppressor p53 Gupta, S Radha, V Furukawa, Y Swarup, G J. Biol. Chem. 276:10585-8 inferred by electronic annotation IEA GO IEA Regulation of TP53 Activity Regulation of TP53 Activity This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Regulation of TP53 Expression and Degradation Regulation of TP53 Expression and Degradation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Regulation of TP53 Degradation Regulation of TP53 Degradation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> MDM2 translocates to the cytosol MDM2 translocates to the cytosol This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10789540 1 nucleoplasm GO 0005654 UniProt:C0H4E7 UniProt C0H4E7 1 EQUAL 491 EQUAL Reactome DB_ID: 10784983 1 1 EQUAL 491 EQUAL Reactome Database ID Release 78 10793088 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10793088 Reactome R-PFA-6795667 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6795667.1 Unphosphorylated MDM2 is exported from the nucleus into the cytosol (Mayo and Donner 2001). 11504915 Pubmed 2001 A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus Mayo, L D Donner, D B Proc. Natl. Acad. Sci. U.S.A. 98:11598-603 inferred by electronic annotation IEA GO IEA MDM2 translocates to the nucleus MDM2 translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10784987 1 O-phospho-L-serine at 166 (in Homo sapiens) 166 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 188 (in Homo sapiens) 188 EQUAL 1 EQUAL 491 EQUAL Reactome DB_ID: 10785624 1 O-phospho-L-serine at 166 (in Homo sapiens) 166 EQUAL O-phospho-L-serine at 188 (in Homo sapiens) 188 EQUAL 1 EQUAL 491 EQUAL Reactome Database ID Release 78 10793086 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10793086 Reactome R-PFA-6793666 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6793666.1 AKT- or SGK1-phosphorylated MDM2 residues S166 and S188 are in the vicinity of the MDM2 nuclear localization signal. MDM2 phosphorylation by AKT or SGK1 leads to MDM2 translocation from the cytosol to the nucleus (Mayo and Donner 2001). inferred by electronic annotation IEA GO IEA MDM2 forms homo- or heterodimers MDM2 forms homo- or heterodimers This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10785624 2 O-phospho-L-serine at 166 (in Homo sapiens) 166 EQUAL O-phospho-L-serine at 188 (in Homo sapiens) 188 EQUAL 1 EQUAL 491 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10794091 1 p-S166,S188-MDM2,MDM4 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-p-S166,S188-MDM2 [nucleoplasm] MDM4 [nucleoplasm] Converted from EntitySet in Reactome Reactome DB_ID: 10794095 1 p-S166,S188-MDM2 dimer, p-S166,S188-MDM2:MDM4 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 78 10794097 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794097 Reactome R-PFA-6804741 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6804741.1 To efficiently function as an E3 ubiquitin ligase, MDM2 has to form dimers or higher order oligomers. MDM2 can homodimerize (Cheng et al. 2011) or heterodimerize with MDM4 (MDMX) (Sharp et al. 1999, Huang et al. 2011, Pant et al. 2011). Dimerization involves the RING domain of MDM2 and/or MDM4. Heterodimers of MDM2 and MDM4 may be particularly important during embryonic development (Pant et al. 2011). 21730132 Pubmed 2011 Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability Pant, Vinod Xiong, Shunbin Iwakuma, Tomoo Quintás-Cardama, Alfonso Lozano, Guillermina Proc. Natl. Acad. Sci. U.S.A. 108:11995-2000 21730163 Pubmed 2011 The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo Huang, Lei Yan, Zheng Liao, Xiaodong Li, Yuan Yang, Jie Wang, Zhu-Gang Zuo, Yong Kawai, Hidehiko Shadfan, Miriam Ganapathy, Suthakar Yuan, Zhi-Min Proc. Natl. Acad. Sci. U.S.A. 108:12001-6 10608892 Pubmed 1999 Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein Sharp, D A Kratowicz, S A Sank, M J George, D L J. Biol. Chem. 274:38189-96 21986495 Pubmed 2011 Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage Cheng, Qian Cross, Brittany Li, Baozong Chen, Lihong Li, Zhenyu Chen, Jiandong Mol. Cell. Biol. 31:4951-63 inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation of MDM4 by CHEK2 Phosphorylation of MDM4 by CHEK2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10785629 1 p-S166,S188-MDM2:p-S403-MDM4 [nucleoplasm] p-S166,S188-MDM2:p-S403-MDM4 Reactome DB_ID: 10785627 1 O-phospho-L-serine at 403 (in Homo sapiens) 403 EQUAL 1 EQUAL 490 EQUAL Reactome DB_ID: 10785624 1 O-phospho-L-serine at 166 (in Homo sapiens) 166 EQUAL O-phospho-L-serine at 188 (in Homo sapiens) 188 EQUAL 1 EQUAL 491 EQUAL Reactome Database ID Release 78 10785629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10785629 Reactome R-PFA-6804939 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6804939.1 Reactome DB_ID: 29358 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 113582 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 10785635 1 p-S166,S188-MDM2:p-S346,S367,S403-MDM4 [nucleoplasm] p-S166,S188-MDM2:p-S346,S367,S403-MDM4 Reactome DB_ID: 10785633 1 O-phospho-L-serine at 342 (in Homo sapiens) 342 EQUAL O-phospho-L-serine at 367 (in Homo sapiens) 367 EQUAL O-phospho-L-serine at 403 (in Homo sapiens) 403 EQUAL 1 EQUAL 490 EQUAL Reactome DB_ID: 10785624 1 O-phospho-L-serine at 166 (in Homo sapiens) 166 EQUAL O-phospho-L-serine at 188 (in Homo sapiens) 188 EQUAL 1 EQUAL 491 EQUAL Reactome Database ID Release 78 10785635 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10785635 Reactome R-PFA-6804936 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6804936.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10785644 UniProt:Q8ILL6 UniProt Q8ILL6 O-phospho-L-threonine at 68 (in Homo sapiens) 68 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 379 (in Homo sapiens) 379 EQUAL O-phospho-L-threonine at 383 (in Homo sapiens) 383 EQUAL O-phospho-L-threonine at 387 (in Homo sapiens) 387 EQUAL 1 EQUAL 543 EQUAL GO 0004674 GO molecular function Reactome Database ID Release 78 10785645 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10785645 Reactome Database ID Release 78 10785647 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10785647 Reactome R-PFA-349426 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-349426.1 CHEK2 (Chk2) kinase is required for phosphorylation of MDM4 at serine residues S342 and S367 in vivo. CHEK2-mediated phosphorylation stimulates MDM4 ubiquitination by MDM2 and subsequent degradation (Chen et al. 2005). 16163388 Pubmed 2005 ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage Chen, L Gilkes, DM Pan, Y Lane, WS Chen, J EMBO J 24:3411-22 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797320 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797320 Reactome R-PFA-6804757 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6804757.1 In unstressed cells, TP53 (p53) has a short half-life as it undergoes rapid ubiquitination and proteasome-mediated degradation. The E3 ubiquitin ligase MDM2, which is a transcriptional target of TP53, plays the main role in TP53 protein down-regulation (Wu et al. 1993). MDM2 forms homodimers and homo-oligomers, but also functions as a heterodimer/hetero-oligomer with MDM4 (MDMX) (Sharp et al. 1999, Cheng et al. 2011, Huang et al. 2011, Pant et al. 2011). The heterodimers of MDM2 and MDM4 may be especially important for downregulation of TP53 during embryonic development (Pant et al. 2011).<p>The nuclear localization of MDM2 is positively regulated by AKT- or SGK1- mediated phosphorylation (Mayo and Donner 2001, Zhou et al. 2001, Amato et al. 2009, Lyo et al. 2010). Phosphorylation of MDM2 by CDK1 or CDK2 decreases affinity of MDM2 for TP53 (Zhang and Prives 2001). ATM and CHEK2 kinases, activated by double strand DNA breaks, phosphorylate TP53, reducing its affinity for MDM2 (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998, Chehab et al. 1999, Chehab et al. 2000). At the same time, ATM phosphorylates MDM2, preventing MDM2 dimerization (Cheng et al. 2009, Cheng et al. 2011). Both ATM and CHEK2 phosphorylate MDM4, triggering MDM2-mediated ubiquitination of MDM4 (Chen et al. 2005, Pereg et al. 2005). Cyclin G1 (CCNG1), transcriptionally induced by TP53, targets the PP2A phosphatase complex to MDM2, resulting in dephosphorylation of MDM2 at specific sites, which can have either a positive or a negative impact on MDM2 function (Okamoto et al. 2002).<p>In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007).<p>In addition to ubiquitinating MDM4 (Pereg et al. 2005), MDM2 can also undergo auto-ubiquitination (Fang et al. 2000). MDM2 and MDM4 can be deubiquitinated by the ubiquitin protease USP2 (Stevenson et al. 2007, Allende-Vega et al. 2010). The ubiquitin protease USP7 can deubiquitinate TP53, but in the presence of DAXX deubiquitinates MDM2 (Li et al. 2002, Sheng et al. 2006, Tang et al. 2006).<p>The tumor suppressor p14-ARF, expressed from the CDKN2A gene in response to oncogenic or oxidative stress, forms a tripartite complex with MDM2 and TP53, sequesters MDM2 from TP53, and thus prevents TP53 degradation (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005).<p>For review of this topic, please refer to Kruse and Gu 2009. 19450511 Pubmed 2009 Modes of p53 regulation Kruse, Jan-Philipp Gu, Wei Cell 137:609-22 8319905 Pubmed 1993 The p53-mdm-2 autoregulatory feedback loop Wu, X Bayle, J H Olson, D Levine, A J Genes Dev. 7:1126-32 19756449 Pubmed 2009 Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation Amato, Rosario D'Antona, Lucia Porciatti, Giovanni Agosti, Valter Menniti, Miranda Rinaldo, Cinzia Costa, Nicola Bellacchio, Emanuele Mattarocci, Stefano Fuiano, Giorgio Soddu, Silvia Paggi, Marco G Lang, F Perrotti, Nicola J. Mol. Med. 87:1221-39 11923872 Pubmed 2002 Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization Li, Muyang Chen, Delin Shiloh, Ariel Luo, Jianyuan Nikolaev, Anatoly Y Qin, J Gu, Wei Nature 416:648-53 19838211 Pubmed 2010 MdmX is a substrate for the deubiquitinating enzyme USP2a Allende-Vega, N Sparks, A Lane, D P Saville, M K Oncogene 29:432-41 17290220 Pubmed 2007 The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2 Stevenson, Lauren F Sparks, Alison Allende-Vega, Nerea Xirodimas, Dimitris P Lane, David P Saville, Mark K EMBO J. 26:976-86 16474402 Pubmed 2006 Molecular recognition of p53 and MDM2 by USP7/HAUSP Sheng, Yi Saridakis, Vivian Sarkari, Feroz Duan, Shili Wu, Tianne Arrowsmith, Cheryl H Frappier, Lori Nat. Struct. Mol. Biol. 13:285-91 16845383 Pubmed 2006 Critical role for Daxx in regulating Mdm2 Tang, Jun Qu, Li-Ke Zhang, Jianke Wang, Wenge Michaelson, Jennifer S Degenhardt, Yan Y El-Deiry, Wafik S Yang, X Nat. Cell Biol. 8:855-62 17121812 Pubmed 2007 CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation Yang, Wensheng Rozan, Laura M McDonald, E Robert Navaraj, Arunasalam Liu, Jue Judy Matthew, Elizabeth M Wang, Wenge Dicker, David T El-Deiry, Wafik S J. Biol. Chem. 282:3273-81 9733515 Pubmed 1998 Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Canman, CE Lim, DS Taya, Y Tamai, K Sakaguchi, K Appella, E Kastan, MB Siliciano, JD Science 281:1677-9 15563468 Pubmed 2005 MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1 Voncken, Jan Willem Niessen, Hanneke Neufeld, Bernd Rennefahrt, Ulrike Dahlmans, Vivian Kubben, Nard Holzer, Barbara Ludwig, Stephan Rapp, Ulf R J. Biol. Chem. 280:5178-87 9843217 Pubmed 1998 ATM associates with and phosphorylates p53: mapping the region of interaction. Khanna, Kum Kum Keating, KE Kozlov, S Scott, S Gatei, M Hobson, K Taya, Y Gabrielli, B Chan, D Lees-Miller, SP Lavin, MF Nat Genet 20:398-400 15788536 Pubmed 2005 Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage Pereg, Y Shkedy, D de Graaf, P Meulmeester, E Edelson-Averbukh, M Salek, M Biton, S Teunisse, AF Lehmann, Wolf Jochemsen, AG Shiloh, Y Proc Natl Acad Sci U S A 102:5056-61 10673500 Pubmed 2000 Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Chehab, NH Malikzay, A Appel, M Halazonetis, TD Genes Dev 14:278-88 9529249 Pubmed 1998 ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways Zhang, Y Xiong, Y Yarbrough, W G Cell 92:725-34 10570149 Pubmed 1999 Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage Chehab, N H Malikzay, A Stavridi, E S Halazonetis, T D Proc. Natl. Acad. Sci. U.S.A. 96:13777-82 20438709 Pubmed 2010 Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway Lyo, Donggon Xu, Limei Foster, David A Biochem. Biophys. Res. Commun. 396:562-5 9733514 Pubmed 1998 Enhanced phosphorylation of p53 by ATM in response to DNA damage. Banin, S Moyal, L Shieh, S Taya, Y Anderson, CW Chessa, L Smorodinsky, NI Prives, C Reiss, Y Shiloh, Y Ziv, Y Science 281:1674-7 11359766 Pubmed 2001 Cyclin a-CDK phosphorylation regulates MDM2 protein interactions Zhang, T Prives, C J. Biol. Chem. 276:29702-10 10722742 Pubmed 2000 Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53 Fang, S Jensen, J P Ludwig, R L Vousden, K H Weissman, A M J. Biol. Chem. 275:8945-51 19816404 Pubmed 2009 ATM activates p53 by regulating MDM2 oligomerization and E3 processivity Cheng, Qian Chen, Lihong Li, Zhenyu Lane, William S Chen, Jiandong EMBO J. 28:3857-67 11883935 Pubmed 2002 Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors Parisi, Tiziana Pollice, Alessandra Di Cristofano, Antonio Calabrò, Viola La Mantia, Girolama Biochem. Biophys. Res. Commun. 291:1138-45 11715018 Pubmed 2001 HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation Zhou, BP Liao, Y Xia, W Zou, Y Spohn, B Hung, MC Nat Cell Biol 3:973-82 11983168 Pubmed 2002 Cyclin G recruits PP2A to dephosphorylate Mdm2 Okamoto, Koji Li, Hongyun Jensen, Michael R Zhang, Tingting Taya, Yoichi Thorgeirsson, Snorri S Prives, Carol Mol. Cell 9:761-71 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797322 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797322 Reactome R-PFA-6806003 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6806003.1 GO 1901796 GO biological process TP53 (p53) tumor suppressor protein is a transcription factor that functions as a homotetramer (Jeffrey et al. 1995). The protein levels of TP53 are low in unstressed cells due to MDM2-mediated ubiquitination that triggers proteasome-mediated degradation of TP53 (Wu et al. 1993). The E3 ubiquitin ligase MDM2 functions as a homodimer/homo-oligomer or a heterodimer/hetero-oligomer with MDM4 (MDMX) (Linares et al. 2003, Toledo and Wahl 2007, Cheng et al. 2011, Wade et al. 2013).<p>Activating phosphorylation of TP53 at serine residues S15 and S20 in response to genotoxic stress disrupts TP53 interaction with MDM2. In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007). Binding of MDM2 to TP53 is also inhibited by the tumor suppressor p14-ARF, transcribed from the CDKN2A gene in response to oncogenic signaling or oxidative stress (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005). Ubiquitin-dependant degradation of TP53 can also be promoted by PIRH2 (Leng et al. 2003) and COP1 (Dornan et al. 2004) ubiquitin ligases. HAUSP (USP7) can deubiquitinate TP53, contributing to TP53 stabilization (Li et al. 2002).<p>While post-translational regulation plays a prominent role, TP53 activity is also controlled at the level of promoter function (reviewed in Saldana-Meyer and Recillas-Targa 2011), mRNA stability and translation efficiency (Mahmoudi et al. 2009, Le et al. 2009, Takagi et al. 2005). 15103385 Pubmed 2004 The ubiquitin ligase COP1 is a critical negative regulator of p53 Dornan, D Wertz, Ingrid Shimizu, Harumi Arnott, David Frantz, Gretchen D Dowd, Patrick O'Rourke, Karen Koeppen, Hartmut Dixit, Vishva M Nature 429:86-92 19293287 Pubmed 2009 MicroRNA-125b is a novel negative regulator of p53 Le, Minh T N Teh, C Shyh-Chang, Ng Xie, Huangming Zhou, Beiyan Korzh, Vladimir Lodish, HF Lim, Bing Genes Dev. 23:862-76 7878469 Pubmed 1995 Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms Jeffrey, PD Gorina, S Pavletich, NP Science 267:1498-502 17499002 Pubmed 2007 MDM2 and MDM4: p53 regulators as targets in anticancer therapy Toledo, Franck Wahl, Geoffrey M Int. J. Biochem. Cell Biol. 39:1476-82 16213212 Pubmed 2005 Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin Takagi, Masatoshi Absalon, Michael J McLure, Kevin G Kastan, Michael B Cell 123:49-63 19250907 Pubmed 2009 Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage Mahmoudi, Salah Henriksson, Sofia Corcoran, Martin Méndez-Vidal, Cristina Wiman, Klas G Farnebo, Marianne Mol. Cell 33:462-71 23303139 Pubmed 2013 MDM2, MDMX and p53 in oncogenesis and cancer therapy Wade, Mark Li, Yao-Cheng Wahl, Geoffrey M Nat. Rev. Cancer 13:83-96 12654245 Pubmed 2003 Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation Leng, Roger P Lin, Yunping Ma, Weili Wu, Hong Lemmers, Benedicte Chung, Stephen Parant, John M Lozano, Guillermina Hakem, Razqallah Benchimol, Samuel Cell 112:779-91 21814038 Pubmed 2011 Transcriptional and epigenetic regulation of the p53 tumor suppressor gene Saldaña-Meyer, Ricardo Recillas-Targa, Félix Epigenetics 6:1068-77 inferred by electronic annotation IEA GO IEA Regulation of TP53 Activity through Phosphorylation Regulation of TP53 Activity through Phosphorylation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CK2 binds FACT CK2 binds FACT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10784020 1 FACT complex [nucleoplasm] FACT complex Reactome DB_ID: 10784013 1 UniProt:Q8IL56 UniProt Q8IL56 2 EQUAL 709 EQUAL Reactome DB_ID: 10784018 1 UniProt:Q8I3T4 UniProt Q8I3T4 2 EQUAL 1047 EQUAL Reactome Database ID Release 78 10784020 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784020 Reactome R-PFA-112417 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-112417.1 Reactome DB_ID: 10794125 1 Casein kinase II [nucleoplasm] Casein kinase II Reactome DB_ID: 10794107 2 UniProt:Q8IDR5 UniProt Q8IDR5 2 EQUAL 215 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10794123 1 CSN2KA dimer [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 78 10794125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794125 Reactome R-PFA-6805066 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6805066.1 Reactome DB_ID: 10794127 1 CK2:FACT [nucleoplasm] CK2:FACT Reactome DB_ID: 10784020 1 Reactome DB_ID: 10794125 1 Reactome Database ID Release 78 10794127 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794127 Reactome R-PFA-6805062 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6805062.1 Reactome Database ID Release 78 10794129 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794129 Reactome R-PFA-6805061 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6805061.1 In response to UV radiation, the casein kinase II (CK2) complex associates with the FACT complex (Keller et al. 2001, Keller and Lu 2002). 12393879 Pubmed 2002 p53 serine 392 phosphorylation increases after UV through induction of the assembly of the CK2.hSPT16.SSRP1 complex Keller, David M Lu, Hua J. Biol. Chem. 277:50206-13 11239457 Pubmed 2001 A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1 Keller, D M Zeng, X Wang, Y Zhang, Q H Kapoor, M Shu, H Goodman, R Lozano, G Zhao, Y Lu, H Mol. Cell 7:283-92 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797826 Reactome R-PFA-6804756 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6804756.1 Phosphorylation of TP53 (p53) at the N-terminal serine residues S15 and S20 plays a critical role in protein stabilization as phosphorylation at these sites interferes with binding of the ubiquitin ligase MDM2 to TP53. Several different kinases can phosphorylate TP53 at S15 and S20. In response to double strand DNA breaks, S15 is phosphorylated by ATM (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998), and S20 by CHEK2 (Chehab et al. 1999, Chehab et al. 2000, Hirao et al. 2000). DNA damage or other types of genotoxic stress, such as stalled replication forks, can trigger ATR-mediated phosphorylation of TP53 at S15 (Lakin et al. 1999, Tibbetts et al. 1999) and CHEK1-mediated phosphorylation of TP53 at S20 (Shieh et al. 2000). In response to various types of cell stress, NUAK1 (Hou et al. 2011), CDK5 (Zhang et al. 2002, Lee et al. 2007, Lee et al. 2008), AMPK (Jones et al. 2005) and TP53RK (Abe et al. 2001, Facchin et al. 2003) can phosphorylate TP53 at S15, while PLK3 (Xie, Wang et al. 2001, Xie, Wu et al. 2001) can phosphorylate TP53 at S20.<p>Phosphorylation of TP53 at serine residue S46 promotes transcription of TP53-regulated apoptotic genes rather than cell cycle arrest genes. Several kinases can phosphorylate S46 of TP53, including ATM-activated DYRK2, which, like TP53, is targeted for degradation by MDM2 (Taira et al. 2007, Taira et al. 2010). TP53 is also phosphorylated at S46 by HIPK2 in the presence of the TP53 transcriptional target TP53INP1 (D'Orazi et al. 2002, Hofmann et al. 2002, Tomasini et al. 2003). CDK5, in addition to phosphorylating TP53 at S15, also phosphorylates it at S33 and S46, which promotes neuronal cell death (Lee et al. 2007).<p>MAPKAPK5 (PRAK) phosphorylates TP53 at serine residue S37, promoting cell cycle arrest and cellular senescence in response to oncogenic RAS signaling (Sun et al. 2007).<p>NUAK1 phosphorylates TP53 at S15 and S392, and phosphorylation at S392 may contribute to TP53-mediated transcriptional activation of cell cycle arrest genes (Hou et al. 2011). S392 of TP53 is also phosphorylated by the complex of casein kinase II (CK2) bound to the FACT complex, enhancing transcriptional activity of TP53 in response to UV irradiation (Keller et al. 2001, Keller and Lu 2002).<p>The activity of TP53 is inhibited by phosphorylation at serine residue S315, which enhances MDM2 binding and degradation of TP53. S315 of TP53 is phosphorylated by Aurora kinase A (AURKA) (Katayama et al. 2004) and CDK2 (Luciani et al. 2000). Interaction with MDM2 and the consequent TP53 degradation is also increased by phosphorylation of TP53 threonine residue T55 by the transcription initiation factor complex TFIID (Li et al. 2004).<p>Aurora kinase B (AURKB) has been shown to phosphorylate TP53 at serine residue S269 and threonine residue T284, which is possibly facilitated by the binding of the NIR co-repressor. AURKB-mediated phosphorylation was reported to inhibit TP53 transcriptional activity through an unknown mechanism (Wu et al. 2011). A putative direct interaction between TP53 and AURKB has also been described and linked to TP53 phosphorylation and S183, T211 and S215 and TP53 degradation (Gully et al. 2012). 10673501 Pubmed 2000 The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Shieh, SY Ahn, J Tamai, K Taya, Y Prives, C Genes Dev 14:289-300 19965871 Pubmed 2010 ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage Taira, Naoe Yamamoto, Hiroyuki Yamaguchi, Tomoko Miki, Yoshio Yoshida, Kiyotsugu J. Biol. Chem. 285:4909-19 22611192 Pubmed 2012 Aurora B kinase phosphorylates and instigates degradation of p53 Gully, Chris P Velazquez-Torres, Guermarie Shin, Ji-Hyun Fuentes-Mattei, Enrique Wang, Edward Carlock, Colin Chen, Jian Rothenberg, Daniel Adams, Henry P Choi, Hyun Ho Guma, Sergei Phan, Liem Chou, Ping-Chieh Su, Chun-Hui Zhang, Fanmao Chen, Jiun-Sheng Yang, Tsung-Ying Yeung, Sai-Ching J Lee, Mong-Hong Proc. Natl. Acad. Sci. U.S.A. 109:E1513-22 14702041 Pubmed 2004 Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53 Katayama, Hiroshi Sasai, Kaori Kawai, Hidehiko Yuan, Zhi-Min Bondaruk, Jolanta Suzuki, Fumio Fujii, Satoshi Arlinghaus, Ralph B Czerniak, Bogdan A Sen, Subrata Nat. Genet. 36:55-62 9925639 Pubmed 1999 A role for ATR in the DNA damage-induced phosphorylation of p53 Tibbetts, R S Brumbaugh, K M Williams, J M Sarkaria, J N Cliby, W A Shieh, SY Taya, Y Prives, C Abraham, Robert T Genes Dev. 13:152-7 11447225 Pubmed 2001 Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3 Xie, S Wang, Q Wu, H Cogswell, J Lu, L Jhanwar-Uniyal, M Dai, W J. Biol. Chem. 276:36194-9 11546806 Pubmed 2001 Cloning and characterization of a p53-related protein kinase expressed in interleukin-2-activated cytotoxic T-cells, epithelial tumor cell lines, and the testes Abe, Y Matsumoto, S Wei, S Nezu, K Miyoshi, A Kito, K Ueda, N Shigemoto, K Hitsumoto, Y Nikawa, J Enomoto, Y J. Biol. Chem. 276:44003-11 11740489 Pubmed 2002 Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2 Hofmann, Thomas G Möller, Andreas Sirma, Hüaeyin Zentgraf, H Taya, Yoichi Dröge, Wulf Will, Hans Schmitz, M Lienhard Nat. Cell Biol. 4:1-10 20959462 Pubmed 2011 Aurora B interacts with NIR-p53, leading to p53 phosphorylation in its DNA-binding domain and subsequent functional suppression Wu, Liming Ma, Chi A Zhao, Yongge Jain, Ashish J. Biol. Chem. 286:2236-44 10710310 Pubmed 2000 DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Hirao, A Kong, YY Matsuoka, S Wakeham, A Ruland, J Yoshida, H Liu, D Elledge, SJ Mak, TW Science 287:1824-7 15866171 Pubmed 2005 AMP-activated protein kinase induces a p53-dependent metabolic checkpoint Jones, Russell G Plas, David R Kubek, Sara Buzzai, Monica Mu, J Xu, Yang Birnbaum, Morris J Thompson, CB Mol. Cell 18:283-93 17591690 Pubmed 2007 Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death Lee, Jong-Hee Kim, Hea-Sook Lee, Sung-Jin Kim, Kyong-Tai J. Cell. Sci. 120:2259-71 11780126 Pubmed 2002 Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis D'Orazi, Gabriella Cecchinelli, Barbara Bruno, Tiziana Manni, Isabella Higashimoto, Yuichiro Saito, Shin'ichi Gostissa, Monica Coen, Sabrina Marchetti, Alessandra Del Sal, Giannino Piaggio, Guilia Fanciulli, Maurizio Appella, E Soddu, Silvia Nat. Cell Biol. 4:11-9 12064478 Pubmed 2002 Cdk5 phosphorylates p53 and regulates its activity Zhang, Jianwen Krishnamurthy, Pavan K Johnson, Gail V W J. Neurochem. 81:307-13 11551930 Pubmed 2001 Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway Xie, S Wu, H Wang, Q Cogswell, J P Husain, I Conn, C Stambrook, P Jhanwar-Uniyal, M Dai, W J. Biol. Chem. 276:43305-12 15053879 Pubmed 2004 Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression Li, Heng-Hong Li, Andrew G Sheppard, Hilary M Liu, Xuan Mol. Cell 13:867-78 10435622 Pubmed 1999 The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53 Lakin, N D Hann, B C Jackson, SP Oncogene 18:3989-95 12914926 Pubmed 2003 Functional homology between yeast piD261/Bud32 and human PRPK: both phosphorylate p53 and PRPK partially complements piD261/Bud32 deficiency Facchin, Sonia Lopreiato, Raffaele Ruzzene, Maria Marin, Oriano Sartori, Geppo Götz, Claudia Montenarh, Mathias Carignani, Giovanna Pinna, Lorenzo A FEBS Lett. 549:63-6 21317932 Pubmed 2011 A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation Hou, X Liu, J-E Liu, W Liu, C-Y Liu, Z-Y Sun, Z-Y Oncogene 30:2933-42 10884347 Pubmed 2000 The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A Luciani, M G Hutchins, J R Zheleva, D Hupp, T R J. Mol. Biol. 300:503-18 18490454 Pubmed 2008 Cooperative roles of c-Abl and Cdk5 in regulation of p53 in response to oxidative stress Lee, Jong-Hee Jeong, Min-Woo Kim, Wanil Choi, Yoon Ha Kim, Kyong-Tai J. Biol. Chem. 283:19826-35 inferred by electronic annotation IEA GO IEA Regulation of TP53 Activity through Acetylation Regulation of TP53 Activity through Acetylation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PI5P Regulates TP53 Acetylation PI5P Regulates TP53 Acetylation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.1.149 PI5P is phosphorylated to PI(4,5)P2 by PIP4K2 dimers in the nucleus PI5P is phosphorylated to PI(4,5)P2 by PIP4K2 dimers in the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 6810408 1 1-phosphatidyl-1D-myo-inositol 5-phosphate [ChEBI:16500] 1-phosphatidyl-1D-myo-inositol 5-phosphate PI5P ChEBI 16500 Reactome DB_ID: 29358 1 Reactome DB_ID: 6810412 1 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate PIP2 ChEBI 18348 Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10794835 PIP4K2 dimers [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0016309 GO molecular function Reactome Database ID Release 78 10794836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794836 Reactome Database ID Release 78 10794838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10794838 Reactome R-PFA-6811522 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6811522.1 In the nucleus, phosphatidylinositol 5-phosphate (PI5P) is phosphorylated to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) mainly by phosphatidylinositol-5-phosphate 4-kinase type-2 beta (PIP4K2B). In the nucleus, PIP4K2B predominantly functions as a homodimer or a heterodimer with PIP4K2A. A low level of PIP4K2A homodimers can also be found in the nucleus. Nuclear localization of PIP4K2C has not been examined but is assumed to be possible, at least through formation of heterodimers with PIP4K2B (Ciruela et al. 2000, Jones et al. 2006, Bultsma et al. 2010). Under conditions of cellular stress, nuclear PIP4K2B can be phosphorylated by p38 MAP kinases, resulting in PIP4K2B inactivation. The putative p38 target site, serine residue S326 of PIP4K2B, is conserved in PIP4K2A, but the role and mechanism of p38-mediated regulation of PIP4K2 isoforms has not been studied in detail (Jones et al. 2006). 20583997 Pubmed 2010 PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha Bultsma, Yvette Keune, Willem-Jan Divecha, Nullin Biochem. J. 430:223-35 10698683 Pubmed 2000 Nuclear targeting of the beta isoform of type II phosphatidylinositol phosphate kinase (phosphatidylinositol 5-phosphate 4-kinase) by its alpha-helix 7 Ciruela, A Hinchliffe, K A Divecha, Nullin Irvine, R F Biochem. J. 346:587-91 16949365 Pubmed 2006 Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta Jones, David R Bultsma, Yvette Keune, Willem-Jan Halstead, Jonathan R Elouarrat, Dallila Mohammed, Shabaz Heck, Albert J D'Santos, Clive S Divecha, Nullin Mol. Cell 23:685-95 inferred by electronic annotation IEA GO IEA 2.7.11 MAP2K6 phosphorylates PIP4K2B MAP2K6 phosphorylates PIP4K2B This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Reactome DB_ID: 10796008 1 PIP4K2B dimers [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 29358 1 Converted from EntitySet in Reactome Reactome DB_ID: 10796019 1 p-S326-PIP4K2B dimers [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10786714 UniProt:Q8IBK6 UniProt Q8IBK6 O-phospho-L-serine at 207 (in Homo sapiens) 207 EQUAL O-phospho-L-threonine at 211 (in Homo sapiens) 211 EQUAL 1 EQUAL 334 EQUAL Reactome Database ID Release 78 10796020 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796020 Reactome Database ID Release 78 10796022 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796022 Reactome R-PFA-8877691 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-8877691.1 Under conditions of cellular stress, such as increased level of reactive oxygen species, MAP2K6 (MKK6), and possibly other kinases of the p38 MAPK family, phosphorylates PIP4K2B at serine residue S326. Threonine residue T322 of PIP4K2B is also phosphorylated under stress conditions, but the responsible kinase is not known. MAP2K6 may also phosphorylate PIP4K2A, but not PIP4K2C (Kuene et al. 2012). 23193159 Pubmed 2012 Regulation of phosphatidylinositol-5-phosphate signaling by Pin1 determines sensitivity to oxidative stress Keune, Willem-Jan Jones, David R Bultsma, Yvette Sommer, Lilly Zhou, Xiao Zhen Lu, Kun Ping Divecha, Nullin Sci Signal 5:ra86 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797842 Reactome R-PFA-6811555 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6811555.1 Under conditions of cellular stress, nuclear levels of phosphatidylinositol-5-phosphate (PI5P) increase and, through interaction with ING2, result in nuclear retention/accumulation of ING2. ING2 binds TP53 (p53) and recruits histone acetyltransferase EP300 (p300) to TP53, leading to TP53 acetylation. Increased nuclear PI5P levels positively regulate TP53 acetylation (Ciruela et al. 2000, Gozani et al. 2003, Jones et al. 2006, Zou et al. 2007, Bultsma et al. 2010). 12859901 Pubmed 2003 The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor Gozani, Or Karuman, Philip Jones, David R Ivanov, Dmitri Cha, James Lugovskoy, Alexey A Baird, Cheryl L Zhu, Hong Field, Seth J Lessnick, Stephen L Villasenor, Jennifer Mehrotra, Bharat Chen, Jian Rao, Vikram R Brugge, Joan S Ferguson, Colin G Payrastre, Bernard Myszka, David G Cantley, Lewis C Wagner, Gerhard Divecha, Nullin Prestwich, Glenn D Yuan, Junying Cell 114:99-111 17940011 Pubmed 2007 Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis Zou, J Marjanovic, Jasna Kisseleva, Marina V Wilson, Monita Majerus, PW Proc. Natl. Acad. Sci. U.S.A. 104:16834-9 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797844 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797844 Reactome R-PFA-6804758 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-6804758.1 Transcriptional activity of TP53 is positively regulated by acetylation of several of its lysine residues. BRD7 binds TP53 and promotes acetylation of TP53 lysine residue K382 by acetyltransferase EP300 (p300). Acetylation of K382 enhances TP53 binding to target promoters, including CDKN1A (p21), MDM2, SERPINE1, TIGAR, TNFRSF10C and NDRG1 (Bensaad et al. 2010, Burrows et al. 2010. Drost et al. 2010). The histone acetyltransferase KAT6A, in the presence of PML, also acetylates TP53 at K382, and, in addition, acetylates K120 of TP53. KAT6A-mediated acetylation increases transcriptional activation of CDKN1A by TP53 (Rokudai et al. 2013). Acetylation of K382 can be reversed by the action of the NuRD complex, containing the TP53-binding MTA2 subunit, resulting in inhibition of TP53 transcriptional activity (Luo et al. 2000). Acetylation of lysine K120 in the DNA binding domain of TP53 by the MYST family acetyltransferases KAT8 (hMOF) and KAT5 (TIP60) can modulate the decision between cell cycle arrest and apoptosis (Sykes et al. 2006, Tang et al. 2006). Studies with acetylation-defective knock-in mutant mice indicate that lysine acetylation in the p53 DNA binding domain acts in part by uncoupling transactivation and transrepression of gene targets, while retaining ability to modulate energy metabolism and production of reactive oxygen species (ROS) and influencing ferroptosis (Li et al. 2012, Jiang et al. 2015). 25799988 Pubmed 2015 Ferroptosis as a p53-mediated activity during tumour suppression Jiang, Le Kon, Ning Li, Tongyuan Wang, Shang-Jui Su, Tao Hibshoosh, Hanina Baer, Richard J Gu, Wei Nature 520:57-62 20660729 Pubmed 2010 Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence Burrows, Anna E Smogorzewska, Agata Elledge, Stephen J Proc. Natl. Acad. Sci. U.S.A. 107:14280-5 20228809 Pubmed 2010 BRD7 is a candidate tumour suppressor gene required for p53 function Drost, Jarno Mantovani, Fiamma Tocco, Francesca Elkon, Ran Comel, Anna Holstege, Henne Kerkhoven, Ron Jonkers, Jos Voorhoeve, P Mathijs Agami, Reuven Del Sal, Giannino Nat. Cell Biol. 12:380-9 23431171 Pubmed 2013 MOZ increases p53 acetylation and premature senescence through its complex formation with PML Rokudai, Susumu Laptenko, Oleg Arnal, Suzzette M Taya, Yoichi Kitabayashi, Issay Prives, Carol Proc. Natl. Acad. Sci. U.S.A. 110:3895-900 11099047 Pubmed 2000 Deacetylation of p53 modulates its effect on cell growth and apoptosis Luo, J Su, F Chen, D Shiloh, A Gu, W Nature 408:377-81 17189187 Pubmed 2006 Acetylation of the p53 DNA-binding domain regulates apoptosis induction Sykes, Stephen M Mellert, Hestia S Holbert, Marc A Li, Keqin Marmorstein, Ronen Lane, William S McMahon, Steven B Mol. Cell 24:841-51 17189186 Pubmed 2006 Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis Tang, Y Luo, Jianyuan Zhang, Wenzhu Gu, Wei Mol. Cell 24:827-39 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797324 Reactome R-PFA-5633007 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-5633007.1 Protein stability and transcriptional activity of TP53 (p53) tumor suppressor are regulated by post-translational modifications that include ubiquitination, phosphorylation, acetylation, methylation, sumoylation and prolyl-isomerization (Kruse and Gu 2009, Meek and Anderson 2009, Santiago et al. 2013, Mantovani et al. 2015). In addition to post-translational modifications, the activity of TP53 is also regulated by binding of transcription co-factors.<p>In unstressed cells, TP53 protein levels are low due to MDM2-mediated ubiquitination of TP53, which triggers proteasome-mediated degradation. In response to stress, TP53 undergoes stabilizing phosphorylation, mainly at serine residues S15 and S20. Several different kinases can phosphorylate TP53 at these sites, but the main S15 kinases are considered to be ATM and ATR, while the main S20 kinases are considered to be CHEK2 and CHEK1. Additional phosphorylation of TP53 at serine residue S46 promotes transcription of pro-apoptotic, rather than cell cycle arrest genes.<p>Acetylation mainly has a positive impact on transcriptional activity of TP53, while methylation can both positively and negatively regulate TP53.<p>Some posttranslational modifications regulate interaction of TP53 with transcriptional co-factors, some of which are themselves transcriptional targets of TP53.<p>For review of the complex network of TP53 regulation, please refer to Kruse and Gu 2009, and Meek and Anderson 2009. 25641576 Pubmed 2015 Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships Mantovani, Fiamma Zannini, Alessandro Rustighi, Alessandra Del Sal, Giannino Biochim. Biophys. Acta 1850:2048-60 20457558 Pubmed 2009 Posttranslational modification of p53: cooperative integrators of function Meek, David W Anderson, Carl W Cold Spring Harb Perspect Biol 1:a000950 23825024 Pubmed 2013 p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1 Santiago, Aleixo Li, Dawei Zhao, Lisa Y Godsey, Adam Liao, Daiqing Mol. Biol. Cell 24:2739-52 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10796830 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796830 Reactome R-PFA-3700989 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-3700989.1 The tumor suppressor TP53 (encoded by the gene p53) is a transcription factor. Under stress conditions, it recognizes specific responsive DNA elements and thus regulates the transcription of many genes involved in a variety of cellular processes, such as cellular metabolism, survival, senescence, apoptosis and DNA damage response. Because of its critical function, p53 is frequently mutated in around 50% of all malignant tumors. For a recent review, please refer to Vousden and Prives 2009 and Kruiswijk et al. 2015. 19410540 Pubmed 2009 Blinded by the Light: The Growing Complexity of p53 Vousden, Karen H Prives, Carol Cell 137:413-31 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10796832 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796832 Reactome R-PFA-212436 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-212436.1 GO 0060260 GO biological process <b>OVERVIEW OF TRANSCRIPTION REGULATION:</b> <br><br>Detailed studies of gene transcription regulation in a wide variety of eukaryotic systems has revealed the general principles and mechanisms by which cell- or tissue-specific regulation of differential gene transcription is mediated (reviewed in Naar, 2001. Kadonaga, 2004, Maston, 2006, Barolo, 2002; Roeder, 2005, Rosenfeld, 2006). Of the three major classes of DNA polymerase involved in eukaryotic gene transcription, Polymerase II generally regulates protein-encoding genes. Figure 1 shows a diagram of the various components involved in cell-specific regulation of Pol-II gene transcription. <br><br>Core Promoter: Pol II-regulated genes typically have a Core Promoter where Pol II and a variety of general factors bind to specific DNA motifs: <br> i: the TATA box (TATA DNA sequence), which is bound by the "TATA-binding protein" (TBP).<br> ii: the Initiator motif (INR), where Pol II and certain other core factors bind, is present in many Pol II-regulated genes.<br> iii: the Downstream Promoter Element (DPE), which is present in a subset of Pol II genes, and where additional core factors bind. <br>The core promoter binding factors are generally ubiquitously expressed, although there are exceptions to this.<br><br>Proximal Promoter: immediately upstream (5') of the core promoter, Pol II target genes often have a Proximal Promoter region that spans up to 500 base pairs (b.p.), or even to 1000 b.p.. This region contains a number of functional DNA binding sites for a specific set of transcription activator (TA) and transcription repressor (TR) proteins. These TA and TR factors are generally cell- or tissue-specific in expression, rather than ubiquitous, so that the presence of their cognate binding sites in the proximal promoter region programs cell- or tissue-specific expression of the target gene, perhaps in conjunction with TA and TR complexes bound in distal enhancer regions. <br><br>Distal Enhancer(s): many or most Pol II regulated genes in higher eukaryotes have one or more distal Enhancer regions which are essential for proper regulation of the gene, often in a cell or tissue-specific pattern. Like the proximal promoter region, each of the distal enhancer regions typically contain a cluster of binding sites for specific TA and/or TR DNA-binding factors, rather than just a single site. <br><br> Enhancers generally have three defining characteristics:<br> i: They can be located very long distances from the promoter of the target gene they regulate, sometimes as far as 100 Kb, or more.<br> ii: They can be either upstream (5') or downstream (3') of the target gene, including within introns of that gene.<br> iii: They can function in either orientation in the DNA.<br><br>Combinatorial mechanisms of transcription regulation: The specific combination of TA and TR binding sites within the proximal promoter and/or distal enhancer(s) provides a "combinatorial transcription code" that mediates cell- or tissue-specific expression of the associated target gene. Each promoter or enhancer region mediates expression in a specific subset of the overall expression pattern. In at least some cases, each enhancer region functions completely independently of the others, so that the overall expression pattern is a linear combination of the expression patterns of each of the enhancer modules.<br><br>Co-Activator and Co-Repressor Complexes: DNA-bound TA and TR proteins typically recruit the assembly of specific Co-Activator (Co-A) and Co-Repressor (Co-R) Complexes, respectively, which are essential for regulating target gene transcription. Both Co-A's and Co-R's are multi-protein complexes that contain several specific protein components.<br><br>Co-Activator complexes generally contain at lease one component protein that has Histone Acetyl Transferase (HAT) enzymatic activity. This functions to acetylate Histones and/or other chromatin-associated factors, which typically increases that transcription activation of the target gene. By contrast, Co-Repressor complexes generally contain at lease one component protein that has Histone De-Acetylase (HDAC) enzymatic activity. This functions to de-acetylate Histones and/or other chromatin-associated factors. This typically increases the transcription repression of the target gene.<br><br>Adaptor (Mediator) complexes: In addition to the co-activator complexes that assemble on particular cell-specific TA factors, - there are at least two additional transcriptional co-activator complexes common to most cells. One of these is the Mediator complex, which functions as an "adaptor" complex that bridges between the tissue-specific co-activator complexes assembled in the proximal promoter (or distal enhancers). The human Mediator complex has been shown to contain at least 19 protein distinct components. Different combinations of these co-activator proteins are also found to be components of specific transcription Co-Activator complexes, such as the DRIP, TRAP and ARC complexes described below. <br><br>TBP/TAF complex: Another large Co-A complex is the "TBP-associated factors" (TAFs) that assemble on TBP (TATA-Binding Protein), which is bound to the TATA box present in many promoters. There are at least 23 human TAF proteins that have been identified. Many of these are ubiquitously expressed, but TAFs can also be expressed in a cell or tissue-specific pattern. <br><br> <b> Specific Coactivator Complexes for DNA-binding Transcription Factors.</b> <br><br>A number of specific co-activator complexes for DNA-binding transcription factors have been identified, including DRIP, TRAP, and ARC (reviewed in Bourbon, 2004, Blazek, 2005, Conaway, 2005, and Malik, 2005). The DRIP co-activator complex was originally identified and named as a specific complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). Similarly, the TRAP co-activator complex was originally identified as a complex that associates with the thyroid receptor (Yuan, 1998). It was later determined that all of the components of the DRIP complex are also present in the TRAP complex, and the ARC complex (discussed further below). For example, the DRIP205 and TRAP220 proteins were show to be identical, as were specific pairs of the other components of these complexes (Rachez, 1999).<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator ("adaptor") complex proteins (reviewed in Bourbon, 2004). The Mediator proteins were originally identified in yeast by Kornberg and colleagues, as complexes associated with DNA polymerase (Kelleher, 1990). In higher organisms, Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (Figure 1). However, many of the Mediator homologues can also be found in complexes associated with specific transcription factors in higher organisms. A unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004). For example, the DRIP205 / TRAP220 proteins are now identified as Mediator 1 (Rachez, 1999), based on homology with yeast Mediator 1.<br><br> <b>Example Pathway: Specific Regulation of Target Genes During Notch Signaling:</b> <br><br>One well-studied example of cell-specific regulation of gene transcription is selective regulation of target genes during Notch signaling. Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL. <br><br>In Drosophila, Su(H) is known to be bifunctional, in that it represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.<br><br>Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).<br><br>In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila. <br><br>During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus (Figure 2). Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-R complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002). <br><br>Thus, CSL is a good example of a bifunctional DNA-binding transcription factor that mediates repression of specific targets genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling. 10235266 Pubmed 1999 Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex Rachez, C Lemon, BD Suldan, Z Bromleigh, V Gamble, M Näär, AM Erdjument-Bromage, H Tempst, P Freedman, LP Nature 398:824-8 16921404 Pubmed 2006 Notch signalling: a simple pathway becomes complex Bray, SJ Nat Rev Mol Cell Biol 7:678-89 14744435 Pubmed 2004 Regulation of RNA polymerase II transcription by sequence-specific DNA binding factors Kadonaga, JT Cell 116:247-57 12023297 Pubmed 2002 Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling Barolo, S Posakony, JW Genes Dev 16:1167-81 16429119 Pubmed 2006 Notch signalling in vertebrate neural development Louvi, A Artavanis-Tsakonas, S Nat Rev Neurosci 7:93-102 15680972 Pubmed 2005 The mammalian Mediator complex Conaway, Joan W Florens, Laurence A Sato, S Tomomori-Sato, C Parmely, TJ Yao, T Swanson, SK Banks, CA Washburn, MP Conaway, Ron C FEBS Lett 579:904-8 16751179 Pubmed 2006 Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response Rosenfeld, MG Lunyak, VV Glass, CK Genes Dev 20:1405-28 14986688 Pubmed 2004 Notch signaling activity Schweisguth, F Curr Biol 14:R129-38 16719718 Pubmed 2006 Transcriptional regulatory elements in the human genome Maston, GA Evans, SK Green, MR Annu Rev Genomics Hum Genet 7:29-59 15680973 Pubmed 2005 Transcriptional regulation and the role of diverse coactivators in animal cells Roeder, RG FEBS Lett 579:909-15 15896744 Pubmed 2005 Dynamic regulation of pol II transcription by the mammalian Mediator complex Malik, S Roeder, RG Trends Biochem Sci 30:256-63 11395415 Pubmed 2001 Transcriptional coactivator complexes Näär, AM Lemon, BD Tjian, R Annu Rev Biochem 70:475-501 15690163 Pubmed 2005 The mediator of RNA polymerase II Blazek, E Mittler, G Meisterernst, M Chromosoma 113:399-408 15175151 Pubmed 2004 A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II Bourbon, HM Aguilera, Andrés Ansari, AZ Asturias, FJ Berk, AJ Bjorklund, S Blackwell, TK Borggrefe, T Carey, M Carlson, M Conaway, Joan W Conaway, Ron C Emmons, SW Fondell, JD Freedman, LP Fukasawa, T Gustafsson, CM Han, M He, X Herman, PK Hinnebusch, Alan G Holmberg, S Holstege, FC Jaehning, JA Kim, YJ Kuras, L Leutz, A Lis, JT Meisterernest, M Naar, AM Nasmyth, K Parvin, JD Ptashne, M Reinberg, Danny Ronne, H Sadowski, I Sakurai, H Sipiczki, M Sternberg, PW Stillman, DJ Strich, R Struhl, K Svejstrup, JQ Tuck, S Winston, F Roeder, RG Kornberg, RD Mol Cell 14:553-7 11861166 Pubmed 2002 Variations on the Notch pathway in neural development Justice, NJ Jan, YN Curr Opin Neurobiol 12:64-70 inferred by electronic annotation IEA GO IEA RNA Polymerase II Pre-transcription Events RNA Polymerase II Pre-transcription Events This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Formation of DSIF complex Formation of DSIF complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10783971 1 UniProt:Q8IJA5 UniProt Q8IJA5 1 EQUAL 117 EQUAL Reactome DB_ID: 10783977 1 UniProt:C6KSV4 UniProt C6KSV4 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 1087 EQUAL Reactome DB_ID: 10783979 1 DSIF complex [nucleoplasm] DSIF complex Reactome DB_ID: 10783971 1 1 EQUAL 117 EQUAL Reactome DB_ID: 10783977 1 phosphorylated residue at unknown position 1 EQUAL 1087 EQUAL Reactome Database ID Release 78 10783979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783979 Reactome R-PFA-112420 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-112420.1 Reactome Database ID Release 78 10784029 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784029 Reactome R-PFA-112434 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-112434.1 At the beginning of this reaction, 1 molecule of 'SUPT5H protein', and 1 molecule of 'SPT4H1 protein' are present. At the end of this reaction, 1 molecule of 'DSIF complex' is present (Wada et al. 1998).<br><br> This reaction takes place in the 'nucleus'.<br> 9450929 Pubmed 1998 DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Wada, T Takagi, T Yamaguchi, Y Ferdous, A Imai, T Hirose, S Sugimoto, S Yano, K Hartzog, GA Winston, F Buratowski, Stephen Handa, Hiroshi Genes Dev 12:343-56 inferred by electronic annotation IEA GO IEA Formation of FACT complex Formation of FACT complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10784013 1 2 EQUAL 709 EQUAL Reactome DB_ID: 10784018 1 2 EQUAL 1047 EQUAL Reactome DB_ID: 10784020 1 Reactome Database ID Release 78 10784022 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784022 Reactome R-PFA-112429 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-112429.1 At the beginning of this reaction, 1 molecule of 'FACT 140 kDa subunit', and 1 molecule of 'FACT 80 kDa subunit' are present. At the end of this reaction, 1 molecule of 'FACT complex' is present.<br><br> This reaction takes place in the 'nucleus' (Kamakaka et al.1993, Orphanides et al.1998).<br> 9489704 Pubmed 1998 FACT, a factor that facilitates transcript elongation through nucleosomes Orphanides, G LeRoy, G Chang, C H Luse, DS Reinberg, D Cell 92:105-16 8370526 Pubmed 1993 Potentiation of RNA polymerase II transcription by Gal4-VP16 during but not after DNA replication and chromatin assembly Kamakaka, R T Bulger, M Kadonaga, J T Genes Dev. 7:1779-95 inferred by electronic annotation IEA GO IEA Abortive termination of early transcription elongation by DSIF:NELF Abortive termination of early transcription elongation by DSIF:NELF This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10784008 1 DSIF:NELF:early elongation complex [nucleoplasm] DSIF:NELF:early elongation complex Reactome DB_ID: 10784006 1 NELF complex [nucleoplasm] NELF complex Reactome DB_ID: 10783994 1 Ghost homologue of NELFB [nucleoplasm] Ghost homologue of NELFB Reactome DB_ID: 10783992 1 Ghost homologue of NELFA [nucleoplasm] Ghost homologue of NELFA Reactome DB_ID: 10783999 1 UniProt:Q9U0K9 UniProt Q9U0K9 1 EQUAL 590 EQUAL Reactome DB_ID: 10784004 1 UniProt:C6KSQ9 UniProt C6KSQ9 1 EQUAL 380 EQUAL Reactome Database ID Release 78 10784006 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784006 Reactome R-PFA-112432 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-112432.1 Reactome DB_ID: 10783990 1 RNA Pol II (hypophosphorylated) complex bound to DSIF protein [nucleoplasm] RNA Pol II (hypophosphorylated) complex bound to DSIF protein Reactome DB_ID: 10783988 1 RNA Pol II (hypophosphorylated):capped pre-mRNA complex [nucleoplasm] RNA Pol II (hypophosphorylated):capped pre-mRNA complex Reactome DB_ID: 10782333 1 Cap Binding Complex (CBC) [nucleoplasm] Cap Binding Complex (CBC) Reactome DB_ID: 10782326 1 UniProt:Q8I1T2 UniProt Q8I1T2 1 EQUAL 156 EQUAL Reactome DB_ID: 10782331 1 UniProt:A0A5K1K8X7 UniProt A0A5K1K8X7 1 EQUAL 790 EQUAL Reactome Database ID Release 78 10782333 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10782333 Reactome R-PFA-77088 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-77088.1 Reactome DB_ID: 10783986 1 UniProt:Q8IJR8 UniProt Q8IJR8 1 EQUAL 961 EQUAL Reactome DB_ID: 10783981 1 RNA Polymerase II holoenzyme complex (hypophosphorylated):TFIIF complex [nucleoplasm] RNA Polymerase II holoenzyme complex (hypophosphorylated):TFIIF complex Reactome DB_ID: 10782391 1 UniProt:Q8IC08 UniProt Q8IC08 1 EQUAL 67 EQUAL Reactome DB_ID: 10782339 1 UniProt:O77375 UniProt O77375 O-phospho-L-serine at 5 (in Homo sapiens) 5 EQUAL 1 EQUAL 1970 EQUAL Reactome DB_ID: 10782354 1 UniProt:O96236 UniProt O96236 1 EQUAL 1174 EQUAL Reactome DB_ID: 10782344 1 UniProt:Q8IER7 UniProt Q8IER7 1 EQUAL 117 EQUAL Reactome DB_ID: 10782349 1 UniProt:Q8I241 UniProt Q8I241 1 EQUAL 125 EQUAL Reactome DB_ID: 10782364 1 UniProt:Q8IJC9 UniProt Q8IJC9 1 EQUAL 172 EQUAL Reactome DB_ID: 10782381 1 UniProt:Q8ID59 UniProt Q8ID59 1 EQUAL 210 EQUAL Reactome DB_ID: 10782366 1 Ghost homologue of POLR2C [nucleoplasm] Ghost homologue of POLR2C Reactome DB_ID: 10782359 1 UniProt:O96150 UniProt O96150 1 EQUAL 142 EQUAL Reactome DB_ID: 10782371 1 UniProt:Q8I5R8 UniProt Q8I5R8 2 EQUAL 150 EQUAL Reactome DB_ID: 10782399 1 TFIIF [nucleoplasm] TFIIF Reactome DB_ID: 10782397 1 Ghost homologue of GTF2F2 [nucleoplasm] Ghost homologue of GTF2F2 Reactome DB_ID: 10782395 1 Ghost homologue of GTF2F1 [nucleoplasm] Ghost homologue of GTF2F1 Reactome Database ID Release 78 10782399 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10782399 Reactome R-PFA-109631 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-109631.1 Reactome DB_ID: 10782376 1 UniProt:Q8IDR2 UniProt Q8IDR2 1 EQUAL 58 EQUAL Reactome DB_ID: 10782386 1 UniProt:O77315 UniProt O77315 2 EQUAL 127 EQUAL Reactome Database ID Release 78 10783981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783981 Reactome R-PFA-113427 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113427.1 Reactome DB_ID: 72085 1 capped pre-mRNA [nucleoplasm] capped pre-mRNA Reactome Database ID Release 78 10783988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783988 Reactome R-PFA-113715 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113715.1 Reactome DB_ID: 10783979 1 Reactome Database ID Release 78 10783990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783990 Reactome R-PFA-113406 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113406.1 Reactome Database ID Release 78 10784008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784008 Reactome R-PFA-113408 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113408.1 Reactome DB_ID: 10784008 1 Reactome Database ID Release 78 10784033 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784033 Reactome R-PFA-113409 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113409.1 In the early elongation phase, shorter transcripts typically of ~30 nt in length are generated due to random termination of elongating nascent transcripts. This abortive cessation of elongation has been observed mainly in the presence of DSIF-NELF bound to Pol II complex. (Reviewed in Conaway et al.,2000; Shilatifard et al., 2003 ). 12676794 Pubmed 2003 The RNA polymerase II elongation complex. Shilatifard, A Conaway, Ron C Conaway, Joan W Annu Rev Biochem 72:693-715 10916156 Pubmed 2000 Control of elongation by RNA polymerase II. Conaway, Joan W Shilatifard, A Dvir, A Conaway, Ron C Trends Biochem Sci 25:375-80 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797070 Reactome R-PFA-674695 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-674695.1 For initiation, Pol II assembles with the general transcription factors TFIIB, TFIID, TFIIE, TFIIF and TFIIH, which are collectively known as the general transcription factors, at promoter DNA to form the pre-initiation complex (PIC). Until the nascent transcript is about 15 nucleotides long, the early transcribing complex is functionally unstable. In the beginning, short RNAs are frequently released and Pol II has to restart transcription (abortive cycling). There is a decline in the level of abortive transcription when the RNA reaches a length of about four nucleotides, and this transition is termed escape commitment 14969722 Pubmed 2004 Structure and function of RNA polymerase II Cramer, P Adv. Protein Chem. 67:1-42 inferred by electronic annotation IEA GO IEA RNA Polymerase II Transcription Initiation And Promoter Clearance RNA Polymerase II Transcription Initiation And Promoter Clearance This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> RNA Polymerase II Promoter Escape RNA Polymerase II Promoter Escape This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.7.7.6 Addition of nucleotides 10 and 11 on the growing transcript: Third Transition Addition of nucleotides 10 and 11 on the growing transcript: Third Transition This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10783448 1 pol II transcription complex containing 9 nucleotide long transcript [nucleoplasm] pol II transcription complex containing 9 nucleotide long transcript Reactome DB_ID: 10782411 1 RNA Polymerase II (unphosphorylated):TFIIF complex [nucleoplasm] RNA Polymerase II (unphosphorylated):TFIIF complex Reactome DB_ID: 10782399 1 Reactome DB_ID: 10782409 1 RNA Polymerase II holoenzyme complex (unphosphorylated) [nucleoplasm] RNA Polymerase II holoenzyme complex (unphosphorylated) Reactome DB_ID: 10782407 1 1 EQUAL 1970 EQUAL Reactome DB_ID: 10782364 1 1 EQUAL 172 EQUAL Reactome DB_ID: 10782391 1 1 EQUAL 67 EQUAL Reactome DB_ID: 10782366 1 Reactome DB_ID: 10782381 1 1 EQUAL 210 EQUAL Reactome DB_ID: 10782359 1 1 EQUAL 142 EQUAL Reactome DB_ID: 10782371 1 2 EQUAL 150 EQUAL Reactome DB_ID: 10782354 1 1 EQUAL 1174 EQUAL Reactome DB_ID: 10782344 1 1 EQUAL 117 EQUAL Reactome DB_ID: 10782376 1 1 EQUAL 58 EQUAL Reactome DB_ID: 10782386 1 2 EQUAL 127 EQUAL Reactome DB_ID: 10782349 1 1 EQUAL 125 EQUAL Reactome Database ID Release 78 10782409 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10782409 Reactome R-PFA-113401 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113401.1 Reactome Database ID Release 78 10782411 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10782411 Reactome R-PFA-71307 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-71307.1 Reactome DB_ID: 75888 1 template DNA:9 nucleotide transcript hybrid [nucleoplasm] template DNA:9 nucleotide transcript hybrid Reactome DB_ID: 10783446 1 TFIIH [nucleoplasm] TFIIH Reactome DB_ID: 10783412 1 CAK [nucleoplasm] CAK Reactome DB_ID: 10783410 1 UniProt:Q8I3Y3 UniProt Q8I3Y3 1 EQUAL 309 EQUAL Reactome DB_ID: 10783405 1 Ghost homologue of CCNH [nucleoplasm] Ghost homologue of CCNH Reactome DB_ID: 10783403 1 Ghost homologue of CDK7 [nucleoplasm] Ghost homologue of CDK7 Reactome Database ID Release 78 10783412 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783412 Reactome R-PFA-69221 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-69221.1 Reactome DB_ID: 10783437 1 UniProt:Q8I4Y8 UniProt Q8I4Y8 1 EQUAL 462 EQUAL Reactome DB_ID: 10783439 1 Ghost homologue of GTF2H1 [nucleoplasm] Ghost homologue of GTF2H1 Reactome DB_ID: 10783422 1 UniProt:Q8IJ31 UniProt Q8IJ31 1 EQUAL 782 EQUAL Reactome DB_ID: 10783432 1 UniProt:Q8IEG6 UniProt Q8IEG6 1 EQUAL 395 EQUAL Reactome DB_ID: 10783444 1 UniProt:Q8IL51 UniProt Q8IL51 1 EQUAL 71 EQUAL Reactome DB_ID: 10783427 1 UniProt:Q8IDG5 UniProt Q8IDG5 1 EQUAL 308 EQUAL Reactome DB_ID: 10783417 1 UniProt:Q8I2H7 UniProt Q8I2H7 1 EQUAL 760 EQUAL Reactome Database ID Release 78 10783446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783446 Reactome R-PFA-109634 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-109634.1 Reactome Database ID Release 78 10783448 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783448 Reactome R-PFA-75882 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-75882.1 Converted from EntitySet in Reactome Reactome DB_ID: 30595 2 NTP [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GTP [nucleoplasm] UTP [nucleoplasm] ATP [nucleoplasm] CTP [nucleoplasm] ChEBI 37565 ChEBI 46398 ChEBI 37563 Reactome DB_ID: 10783450 1 pol II transcription complex containing 11 nucleotide long transcript [nucleoplasm] pol II transcription complex containing 11 nucleotide long transcript Reactome DB_ID: 10782411 1 Reactome DB_ID: 75901 1 template DNA:11 nucleotide transcript hybrid [nucleoplasm] template DNA:11 nucleotide transcript hybrid Reactome DB_ID: 10783446 1 Reactome Database ID Release 78 10783450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783450 Reactome R-PFA-75902 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-75902.1 Reactome DB_ID: 113541 2 diphosphate(3-) [ChEBI:33019] diphosphate(3-) ChEBI 33019 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10782411 GO 0003899 GO molecular function Reactome Database ID Release 78 10783451 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783451 Reactome Database ID Release 78 10783453 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783453 Reactome R-PFA-76576 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-76576.1 Formation of phosphodiester bonds nine and ten creates RNA products, which do not dissociate from the RNA pol II initiation complex. The transcription complex has enter the productive elongation phase. TFIIH and ATP-hydrolysis are required for efficient promoter escape. The open region (“transcription bubble”) expands concomitant with the site of RNA-extension. The region upstream from the transcription start site (-9 to -3) collapses to the double-stranded state. TFIIH remains associated to the RNA pol II initiation complex. 7601352 Pubmed 1995 Recycling of the general transcription factors during RNA polymerase II transcription. Zawel, L Kumar, KP Reinberg, Danny Genes Dev 9:1479-90 9405375 Pubmed 1998 Three transitions in the RNA polymerase II transcription complex during initiation. Holstege, FC Fiedler, U Timmers, HT EMBO J 16:7468-80 inferred by electronic annotation IEA GO IEA 2.7.7.6 Addition of nucleotides between position +11 and +30 Addition of nucleotides between position +11 and +30 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10783450 1 Converted from EntitySet in Reactome Reactome DB_ID: 30595 1 Reactome DB_ID: 10783475 1 Pol II transcription complex containing extruded transcript to +30 [nucleoplasm] Pol II transcription complex containing extruded transcript to +30 Reactome DB_ID: 111260 1 template DNA:30 nt transcript hybrid [nucleoplasm] template DNA:30 nt transcript hybrid Reactome DB_ID: 10782411 1 Reactome DB_ID: 10783446 1 Reactome Database ID Release 78 10783475 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783475 Reactome R-PFA-157171 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-157171.1 Reactome DB_ID: 113541 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10782411 Reactome Database ID Release 78 10783783 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783783 Reactome R-PFA-111264 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-111264.1 RNA polymerase II transcription complexes are susceptible to transcriptional stalling and arrest, when extending nascent transcripts to 30-nt. This susceptibility depends on presence on down-stream DNA, the particular DNA-sequence of the template and presence of transcription factors. Transcription factor TFIIH remains associated to the RNA pol II elongation complex until position +30. At this stage transcription elongation factor TFIIS can rescue stalled transcription elongation complexes. The transcription bubble varies between 13- and 22-nt in size. 11486021 Pubmed 2001 Promoter clearance by RNA polymerase II is an extended, multistep process strongly affected by sequence. Pal, M McKean, D Luse, DS Mol Cell Biol 21:5815-25 11433015 Pubmed 2001 Analysis of the open region of RNA polymerase II transcription complexes in the early phase of elongation. Fiedler, U Timmers, HT Nucleic Acids Res 29:2706-14 9353262 Pubmed 1997 Promoter escape by RNA polymerase II. Formation of an escape-competent transcriptional intermediate is a prerequisite for exit of polymerase from the promoter. Dvir, A Tan, S Conaway, Joan W Conaway, Ron C J Biol Chem 272:28175-8 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10796966 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796966 Reactome R-PFA-73776 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-73776.1 GO 0006368 GO biological process RNA Polymerase II promoter escape occurs after the first phosphodiester bond has been created. inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10796968 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796968 Reactome R-PFA-76042 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-76042.1 The transcription cycle is divided in three major phases: initiation, elongation, and termination. Transcription initiation include promoter DNA binding, DNA melting, and initial synthesis of short RNA transcripts. Many changes must occur to the RNA polymerase II (pol II) transcription complex as it makes the transition from initiation into transcript elongation. During this intermediate phase of transcription, contact with initiation factors is lost and stable association with the nascent transcript is established. These changes collectively comprise promoter clearance. 22982364 Pubmed 2013 Promoter clearance by RNA polymerase II Luse, Donal S Biochim. Biophys. Acta 1829:63-8 inferred by electronic annotation IEA GO IEA RNA Pol II CTD phosphorylation and interaction with CE RNA Pol II CTD phosphorylation and interaction with CE This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Extrusion of 5'-end of 30 nt long transcript through the pore in Pol II complex Extrusion of 5'-end of 30 nt long transcript through the pore in Pol II complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10783475 1 Reactome DB_ID: 10783475 1 Reactome Database ID Release 78 10784035 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784035 Reactome R-PFA-113430 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113430.1 At the beginning of this reaction, 1 molecule of 'Pol II transcription complex containing transcript to +30' is present. At the end of this reaction, 1 molecule of 'Pol II transcription complex containing extruded transcript to +30' is present.<br><br> This reaction takes place in the 'nucleus' (Buratowski 2009). 19941815 Pubmed 2009 Progression through the RNA polymerase II CTD cycle Buratowski, Stephen Mol. Cell 36:541-6 inferred by electronic annotation IEA GO IEA 2.7.11 Phosphorylation (Ser5) of RNA pol II CTD Phosphorylation (Ser5) of RNA pol II CTD This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10783475 1 Reactome DB_ID: 29358 1 Reactome DB_ID: 10783477 1 Pol II transcription complex with (ser5) phosphorylated CTD containing extruded transcript to +30 [nucleoplasm] Pol II transcription complex with (ser5) phosphorylated CTD containing extruded transcript to +30 Reactome DB_ID: 111260 1 Reactome DB_ID: 10782401 1 RNA polymerase II (phosphorylated):TFIIF complex [nucleoplasm] RNA polymerase II (phosphorylated):TFIIF complex Reactome DB_ID: 10782399 1 Reactome DB_ID: 10782393 1 RNA Polymerase II holoenzyme complex (phosphorylated) [nucleoplasm] RNA Polymerase II holoenzyme complex (phosphorylated) Reactome DB_ID: 10782364 1 1 EQUAL 172 EQUAL Reactome DB_ID: 10782391 1 1 EQUAL 67 EQUAL Reactome DB_ID: 10782366 1 Reactome DB_ID: 10782381 1 1 EQUAL 210 EQUAL Reactome DB_ID: 10782359 1 1 EQUAL 142 EQUAL Reactome DB_ID: 10782339 1 O-phospho-L-serine at 5 (in Homo sapiens) 5 EQUAL 1 EQUAL 1970 EQUAL Reactome DB_ID: 10782371 1 2 EQUAL 150 EQUAL Reactome DB_ID: 10782354 1 1 EQUAL 1174 EQUAL Reactome DB_ID: 10782344 1 1 EQUAL 117 EQUAL Reactome DB_ID: 10782376 1 1 EQUAL 58 EQUAL Reactome DB_ID: 10782386 1 2 EQUAL 127 EQUAL Reactome DB_ID: 10782349 1 1 EQUAL 125 EQUAL Reactome Database ID Release 78 10782393 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10782393 Reactome R-PFA-113716 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113716.1 Reactome Database ID Release 78 10782401 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10782401 Reactome R-PFA-113404 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113404.1 Reactome DB_ID: 10783446 1 Reactome Database ID Release 78 10783477 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783477 Reactome R-PFA-157174 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-157174.1 Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10783475 Reactome Database ID Release 78 10783478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783478 Reactome Database ID Release 78 10783480 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10783480 Reactome R-PFA-77071 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-77071.1 Phosphorylation of serine 5 residue at the CTD of pol II largest subunit is an important step signaling the end of initiation and escape into processive elongation processes. Cdk7 protein subunit of TFIIH phosphorylates RNA Pol II CTD serine 5 residues on its heptad repeats (Buratowski 2009). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10796970 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796970 Reactome R-PFA-77075 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-77075.1 To facilitate co-transcriptional capping, and thereby restrict the cap structure to RNAs made by RNA polymerase II, the capping enzymes bind directly to the RNA polymerase II. The C-terminal domain of the largest Pol II subunit contains several phosphorylation sites on its heptapeptide repeats. The capping enzyme guanylyltransferase and the methyltransferase bind specifically to CTD phosphorylated at Serine 5 within the CTD. Kinase subunit of TFIIH, Cdk7, catalyzes this phosphorylation event that occurs near the promoter. In addition, it has been shown that binding of capping enzyme to the Serine-5 phosphorylated CTD stimulates guanylyltransferase activity in vitro. inferred by electronic annotation IEA GO IEA RNA Polymerase II Transcription Elongation RNA Polymerase II Transcription Elongation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Formation of the Early Elongation Complex Formation of the Early Elongation Complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> DSIF complex binds to RNA Pol II (hypophosphorylated) DSIF complex binds to RNA Pol II (hypophosphorylated) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10783988 1 Reactome DB_ID: 10783979 1 Reactome DB_ID: 10783990 1 Reactome Database ID Release 78 10784031 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784031 Reactome R-PFA-113407 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113407.1 DSIF is a heterodimer consisting of hSPT4 (human homolog of yeast Spt4- p14) and hSPT5 (human homolog of yeast Spt5-p160). DSIF association with Pol II may be enabled by Spt5 binding to Pol II creating a scaffold for NELF binding (Wada et al.,1998). Spt5 subunit of DSIF can be phosphorylated by P-TEFb. 12653964 Pubmed 2003 Structure-function analysis of human Spt4: evidence that hSpt4 and hSpt5 exert their roles in transcriptional elongation as parts of the DSIF complex. Kim, DK Inukai, N Yamada, T Furuya, A Sato, H Yamaguchi, Y Wada, T Handa, Hiroshi Genes Cells 8:371-8 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797072 Reactome R-PFA-113418 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-113418.1 Transcription elongation by RNA polymerase II (RNAPII) is controlled by a number of trans-acting transcription elongation factors as well as by cis-acting elements. Transcription elongation is a rate-limiting step for proper mRNA production in which the phosphorylation of Pol II CTD is a crucial biochemical event. The role of CTD phosphorylation in transcription by Pol II is greatly impaired by protein kinase inhibitors such as 5,6-dichloro-1- ribofuranosylbenzimidazole (DRB), which block CTD phosphorylation and induce arrest of elongating Pol II. DRB-sensitive activation Pol II CTD during elongation has enabled the isolation of two sets of factors -Negative Elongation Factors (NELF) and DRB sensitivity inducing factor (DSIF). P-Tefb is a DRB-sensitive, cyclin-dependent CTD kinase composed of Cdk9 that carries out Serine-2 phosphorylation of Pol II CTD during elongation.<BR>The mechanism by which DSIF, NELF and P-TEFb act together in Pol II-regulated elongation is yet to be fully understood. Various biochemical evidences point to a model in which DSIF and NELF negatively regulate elongation through interactions with polymerase containing a hypophosphorylated CTD. Subsequent phosphorylation of the Pol II CTD by P-Tefb might promote elongation by inhibiting interactions of DSIF and NELF with the elongation complex.<BR> 11940650 Pubmed 2002 Evidence that negative elongation factor represses transcription elongation through binding to a DRB sensitivity-inducing factor/RNA polymerase II complex and RNA. Yamaguchi, Y Inukai, N Narita, T Wada, T Handa, Hiroshi Mol Cell Biol 22:2918-27 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797074 Reactome R-PFA-75955 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-75955.1 The mechanisms governing the process of elongation during eukaryotic mRNA synthesis are being unraveled by recent studies. These studies have led to the expected discovery of a diverse collection of transcription factors that directly regulate the activities of RNA Polymerase II and unexpected discovery of roles for many elongation factors in other basic processes like DNA repair, recombination, etc. The transcription machinery and structural features of the major RNA polymerases are conserved across species. The genes active during elongation fall under different classes like, housekeeping, cell-cycle regulated, development and differentiation specific genes etc. The list of genes involved in elongation has been growing in recent times, and include: -TFIIS,DSIF, NELF, P-Tefb etc. that are involved in drug induced or sequence-dependent arrest - TFIIF, ELL, elongin, elongator etc. that are involved in increasing the catalytic rate of elongation by altering the Km and/or the Vmax of Pol II -FACT, Paf1 and other factors that are involved chromatin modification - DNA repair proteins, RNA processing and export factors, the 19S proteasome and a host of other factors like Spt5-Spt5, Paf1, and NELF complexes, FCP1P etc. (Arndt and Kane, 2003). Elongation also represents processive phase of transcription in which the activities of several mRNA processing factors are coupled to transcription through their binding to RNA polymerase (Pol II). One of the key events that enables this interaction is the differential phosphorylation of Pol II CTD. Phosphorylation pattern of CTD changes during transcription, most significantly at the beginning and during elongation process. TFIIH-dependent Ser5 phosphorylation is observed primarily at promoter regions while P-Tefb mediated Ser2 phosphorylation is seen mainly in the coding regions, during elongation. Experimental evidence suggests a dynamic association of RNA processing factors with differently modified forms of the polymerase during the transcription cycle. (Komarnitsky et al., 2000). [Komarnitsky et al 2000, Arndt & Kane 2003, Shilatifard et al 2003] 14550628 Pubmed 2003 Running with RNA polymerase: eukaryotic transcript elongation. Arndt, KM Kane, CM Trends Genet 19:543-50 11018013 Pubmed 2000 Different phosphorylated forms of RNA polymerase II and associated mRNA processing factors during transcription. Komarnitsky, P Cho, EJ Buratowski, Stephen Genes Dev 14:2452-60 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10796834 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796834 Reactome R-PFA-73857 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-73857.1 GO 0006366 GO biological process RNA polymerase II (Pol II) is the central enzyme that catalyses DNA- directed mRNA synthesis during the transcription of protein-coding genes. Pol II consists of a 10-subunit catalytic core, which alone is capable of elongating the RNA transcript, and a complex of two subunits, Rpb4/7, that is required for transcription initiation. <BR> The transcription cycle is divided in three major phases: initiation, elongation, and termination. Transcription initiation include promoter DNA binding, DNA melting, and initial synthesis of short RNA transcripts. The transition from initiation to elongation, is referred to as promoter escape and leads to a stable elongation complex that is characterized by an open DNA region or transcription bubble. The bubble contains the DNA-RNA hybrid, a heteroduplex of eight to nine base pairs. The growing 3-end of the RNA is engaged with the polymerase complex active site. Ultimately transcription terminates and Pol II dissocitates from the template. 26789250 Pubmed 2016 Structure of transcribing mammalian RNA polymerase II Bernecky, Carrie Herzog, Franz Baumeister, Wolfgang Plitzko, Jürgen M Cramer, P Nature 529:551-4 inferred by electronic annotation IEA GO IEA Transcription from mitochondrial promoters Transcription from mitochondrial promoters This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Mitochondrial transcription initiation Mitochondrial transcription initiation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TFAM binds to mitochondrial promoters TFAM binds to mitochondrial promoters This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 163305 1 mitochondrial matrix GO 0005759 mitochondrial DNA promoter [mitochondrial matrix] mitochondrial DNA promoter Reactome DB_ID: 10784274 1 UniProt:Q8I616 UniProt Q8I616 43 EQUAL 246 EQUAL Reactome DB_ID: 10784276 1 TFAM:mitochondrial promoter complex [mitochondrial matrix] TFAM:mitochondrial promoter complex Reactome DB_ID: 163305 1 Reactome DB_ID: 10784274 1 43 EQUAL 246 EQUAL Reactome Database ID Release 78 10784276 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784276 Reactome R-PFA-163298 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-163298.1 Reactome Database ID Release 78 10784301 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784301 Reactome R-PFA-163310 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-163310.1 Studies of human LSP have revealed that a minimal DNA fragment corresponding to position -28 to +16 relative to the transcription initiation site is able to support transcription initiation in a mitochondrial extract (Chang and Clayton, 1984). TFAM interacts directly with nucleotides between positions -35 and -17 (Fisher et al., 1987), and the exact distance between the TFAM-binding site and the transcription start site is essential for promoter activity (Dairaghi et al., 1995). 3594571 Pubmed 1987 Promoter selection in human mitochondria involves binding of a transcription factor to orientation-independent upstream regulatory elements Fisher, RP Topper, JN Cell 50:247-58 7599198 Pubmed 1995 Human mitochondrial transcription factor A and promoter spacing integrity are required for transcription initiation Dairaghi, DJ Shadel, GS Biochim Biophys Acta 1271:127-34 6697390 Pubmed 1984 Precise identification of individual promoters for transcription of each strand of human mitochondrial DNA Chang, DD Cell 36:635-43 inferred by electronic annotation IEA GO IEA Association of TFAM:mt promoter complex with POLRMT:TFB2M Association of TFAM:mt promoter complex with POLRMT:TFB2M This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10784276 1 Reactome DB_ID: 10784295 1 POLRMT:TFB2M complex [mitochondrial matrix] POLRMT:TFB2M complex Reactome DB_ID: 10784281 1 UniProt:Q8IIB0 UniProt Q8IIB0 42 EQUAL 1230 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10784293 1 Homologues of TFB2M [mitochondrial matrix] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TFB2M [mitochondrial matrix] TFB2M [mitochondrial matrix] UniProt A0A144A0V8 UniProt Q8ILT8 Reactome Database ID Release 78 10784295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784295 Reactome R-PFA-163306 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-163306.1 Reactome DB_ID: 10784297 1 POLRMT:TFB2M:TFAM:mitochondrial promoter complex [mitochondrial matrix] POLRMT:TFB2M:TFAM:mitochondrial promoter complex Reactome DB_ID: 10784276 1 Reactome DB_ID: 10784295 1 Reactome Database ID Release 78 10784297 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784297 Reactome R-PFA-163307 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-163307.1 Reactome Database ID Release 78 10784299 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10784299 Reactome R-PFA-163296 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-163296.1 At the beginning of this reaction, 1 molecule of 'POLRMT:TFB2M complex', and 1 molecule of 'TFAM:mitochondrial promoter complex' are present. At the end of this reaction, 1 molecule of 'POLRMT:TFB2M:TFAM:mitochondrial promoter complex' is present.<br><br> This reaction takes place in the 'mitochondrial matrix'.<br> 12068295 Pubmed 2002 Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA Falkenberg, M Gaspari, M Rantanen, A Trifunovic, A Larsson, Nils-Göran Gustafsson, CM Nat Genet 31:289-94 15526033 Pubmed 2004 The mitochondrial RNA polymerase contributes critically to promoter specificity in mammalian cells Gaspari, M Falkenberg, M Larsson, Nils-Göran Gustafsson, CM EMBO J 23:4606-14 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797116 Reactome R-PFA-163282 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-163282.1 GO 0006391 GO biological process Human mtDNA is transcribed by a dedicated mitochondrial RNA polymerase (POLRMT), which displays significant sequence similarity to the monomeric RNA polymerases found in bacteriophages. In contrast to the phage T7 RNA polymerase, POLRMT cannot interact with promoter DNA and initiate transcription on its own, but requires the presence of the mitochondrial transcription factor A (TFAM), and either transcription factor B1 (TFB1M) or B2 (TFB2M). The 4 proteins of the basal mitochondrial transcription machinery have been purified in recombinant form and used to reconstitute transcription in vitro with a promoter containing DNA fragment (Falkenberg et al., 2002). Although both TFB1M and TFB2M can support in vitro transcription with POLRMT, TFB2M is at least two orders of magnitude more active than TFB1M and the physiological role of TFB1M in mitochondrial transcription has not yet been completely defined. The TFB1M and TFB2M display primary sequence similarity to a family of rRNA methyltransferases, which dimethylates two adjacent adenosine bases near the 3' end of the small subunit rRNA during ribosome biogenesis (Falkenberg et al., 2002; McCulloch et al., 2002). Human TFB1M is, in fact, a dual function protein, which not only support mitochondrial transcription in vitro, but also acts as a rRNA methyltransferase (Seidel-Rogol et al., 2003). The methyltransferase activity is not required for transcription, since point mutations in conserved methyltransferase motifs of TFB1M revealed that it stimulates transcription in vitro independently of S-adenosylmethionine binding and rRNA methyltransferase activity. 12525854 Pubmed 2003 Replication and transcription of mammalian mitochondrial DNA Fernandez-Silva, P Enriquez, JA Montoya, J Exp Physiol 88:41-56 12496758 Pubmed 2003 Human mitochondrial transcription factor B1 methylates ribosomal RNA at a conserved stem-loop Seidel-Rogol, BL McCulloch, V Shadel, GS Nat Genet 33:23-4 11041509 Pubmed 2000 Transcription and replication of mitochondrial DNA Clayton, DA Hum Reprod 15:11-7 11809803 Pubmed 2002 A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine McCulloch, V Seidel-Rogol, BL Shadel, GS Mol Cell Biol 22:1116-25 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10797118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10797118 Reactome R-PFA-75944 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-75944.1 GO 0006390 GO biological process Thirteen of the ~80 different proteins present in the respiratory chain of human mitochondria are encoded by the mitochondrial genome (mtDNA). The circular mtDNA, which is present in 1000 to 10000 copies in the human cell, also encodes for 2 ribosomal RNAs, and 22 transfer RNAs. The double-stranded mitochondrial genome lacks introns and the longer non-coding region contains the control elements for transcription and replication of mtDNA (Shadel and Clayton, 1997). The two mtDNA strands are referred to as the heavy (H-strand) and the light (L-strand) due to their differing G+T content. In human cells, each strand contains one single promoter for transcriptional initiation, the light-strand promoter (LSP) or the heavy-strand promoter (HSP). Transcription from the mitochondrial promoters produce polycistronic precursor RNA encompassing all the genetic information encoded in each of the specific strands. The primary transcripts are processed to produce the individual tRNA and mRNA molecules (Clayton, 1991; Ojala et al., 1981). There is likely a second initiation site for heavy strand transcription, which produces RNAs spanning the rDNA region. The resulting transcript including the genes for the two mitochondrial rRNAs and ends at the boundary between the 16 S rRNA and the tRNALeu(UUR) genes (Montoya et al., 1982; Montoya et al.,1983; Christianson and Clayton 1986). The existence of such a separate transcription unit may explain why the steady-state levels of rRNAs are much higher than the steady state levels of mRNAs. 6185947 Pubmed 1982 Identification of initiation sites for heavy-strand and light-strand transcription in human mitochondrial DNA Montoya, J Christianson, T Levens, D Rabinowitz, M Attardi, G Proc Natl Acad Sci U S A 79:7195-9 9242913 Pubmed 1997 Mitochondrial DNA maintenance in vertebrates Shadel, GS Annu Rev Biochem 66:409-35 6883508 Pubmed 1983 The pattern of transcription of the human mitochondrial rRNA genes reveals two overlapping transcription units Montoya, J Gaines, GL Attardi, G Cell 34:151-9 7219536 Pubmed 1981 tRNA punctuation model of RNA processing in human mitochondria Ojala, D Montoya, J Attardi, G Nature 290:470-4 1809353 Pubmed 1991 Replication and transcription of vertebrate mitochondrial DNA Clayton, DA Annu Rev Cell Biol 7:453-78 3018722 Pubmed 1986 In vitro transcription of human mitochondrial DNA: accurate termination requires a region of DNA sequence that can function bidirectionally Christianson, TW Proc Natl Acad Sci U S A 83:6277-81 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 78 10796836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10796836 Reactome R-PFA-74160 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-PFA-74160.1 GO 0006351 GO biological process Gene expression encompasses transcription and translation and the regulation of these processes. RNA Polymerase I Transcription produces the large preribosomal RNA transcript (45S pre-rRNA) that is processed to yield 18S rRNA, 28S rRNA, and 5.8S rRNA, accounting for about half the RNA in a cell. RNA Polymerase II transcription produces messenger RNAs (mRNA) as well as a subset of non-coding RNAs including many small nucleolar RNAs (snRNA) and microRNAs (miRNA). RNA Polymerase III Transcription produces transfer RNAs (tRNA), 5S RNA, 7SL RNA, and U6 snRNA. Transcription from mitochondrial promoters is performed by the mitochondrial RNA polymerase, POLRMT, to yield long transcripts from each DNA strand that are processed to yield 12S rRNA, 16S rRNA, tRNAs, and a few RNAs encoding components of the electron transport chain. Regulation of gene expression can be divided into epigenetic regulation, transcriptional regulation, and post-transcription regulation (comprising translational efficiency and RNA stability). Epigenetic regulation of gene expression is the result of heritable chemical modifications to DNA and DNA-binding proteins such as histones. Epigenetic changes result in altered chromatin complexes that influence transcription. Gene Silencing by RNA mostly occurs post-transcriptionally but can also affect transcription. Small RNAs originating from the genome (miRNAs) or from exogenous RNA (siRNAs) are processed and transferred to the RNA-induced silencing complex (RISC), which interacts with complementary RNA to cause cleavage, translational inhibition, or transcriptional inhibition. inferred by electronic annotation IEA GO IEA