BioPAX pathway converted from "RUNX3 regulates CDKN1A transcription" in the Reactome database.RUNX3 regulates CDKN1A transcriptionRUNX3 regulates CDKN1A transcriptionRUNX3 contributes to the upregulation of the CDKN1A (p21) gene transcription in response to TGF-beta (TGFB1) signaling. RUNX3 binds to SMAD3 and SMAD4, and cooperates with the activated SMAD3:SMAD4 complex in transactivation of CDKN1A. Runx3 knockout mice exhibit decreased sensitivity to TGF-beta and develop gastric epithelial hyperplasia (Chi et al. 2005). In response to TGF-beta signaling, the CBFB:RUNX3 complex binds to the tumor suppressor ZFHX3 (ATBF1) and, through an unknown mechanism, this complex positively regulates the CDKN1A transcription (Mabuchi et al. 2010).<br>In addition, RUNX3 may act as a TP53 co-factor, stimulating TP53-mediated transcription of target genes, including CDKN1A (p21) (Yamada et al. 2010).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31RUNX3 binds SMAD3 and SMAD4RUNX3 binds SMAD3 and SMAD4RUNX3 binds the complex of SMAD3 and SMAD4, formed in response to TGF-beta (TGFB1) signaling (Hanai et al. 1999, Chi et al. 2005).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Reactome DB_ID: 88781531nucleoplasmGO0005654p-2S-SMAD3:p-2S-SMAD3:SMAD4 [nucleoplasm]p-2S-SMAD3:p-2S-SMAD3:SMAD4Reactome DB_ID: 1771042UniProt:P84022 SMAD3SMAD3MADH3SMAD3FUNCTION Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Monomer; in the absence of TGF-beta. Homooligomer; in the presence of TGF-beta. Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex. Interacts with TGFBR1. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3. Interacts with AIP1, TGFB1I1, TTRAP, FOXL2, PML, PRDM16, HGS, WWP1 and SNW1. Interacts (via MH2 domain) with CITED2 (via C-terminus). Interacts with NEDD4L; the interaction requires TGF-beta stimulation. Interacts (via MH2 domain) with ZFYVE9. Interacts with HDAC1, TGIF and TGIF2, RUNX3, CREBBP, SKOR1, SKOR2, SNON, ATF2, SMURF2 and TGFB1I1. Interacts with DACH1; the interaction inhibits the TGF-beta signaling. Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta. Found in a complex with SMAD3, RAN and XPO4. Interacts in the complex directly with XPO4. Interacts (via MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus. Interacts with RBPMS. Interacts (via MH2 domain) with MECOM. Interacts with WWTR1 (via its coiled-coil domain). Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3. This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity. Interacts with SKI; the interaction represses SMAD3 transcriptional activity. Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta. Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling. Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling. Interacts with MEN1. Interacts with IL1F7. Interaction with CSNK1G2. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts with PMEPA1. Interacts with ZC3H3 (By similarity). Interacts with ZNF451 (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with ZFHX3. Interacts weakly with ZNF8 (PubMed:12370310). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (By similarity). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1 (PubMed:24613385). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850).SUBUNIT (Microbial infection) Interacts with SARS-CoV nucleoprotein.DOMAIN The MH1 domain is required for DNA binding. Also binds zinc ions which are necessary for the DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.DOMAIN The linker region is required for the TGFbeta-mediated transcriptional activity and acts synergistically with the MH2 domain.PTM Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G(1)/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated by PDPK1.PTM Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.PTM Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.PTM Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding (PubMed:21947082). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover (By similarity). Undergoes STUB1-mediated ubiquitination and degradation (PubMed:24613385).SIMILARITY Belongs to the dwarfin/SMAD family.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtP84022O-phospho-L-serine at 423423EQUALO-phospho-L-serine [MOD:00046]O-phospho-L-serine at 425425EQUALChain Coordinates1EQUAL425EQUALReactome DB_ID: 1771031UniProt:Q13485 SMAD4SMAD4SMAD4MADH4DPC4FUNCTION In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.SUBUNIT Found in a complex with SMAD1 and YY1 (By similarity). Interacts with CITED2 (By similarity). Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Interacts with ZC3H3 (By similarity). Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (PubMed:24324267). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts weakly with ZNF8 (PubMed:12370310). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (PubMed:25310401). Interacts with DLX1 (PubMed:14671321). Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1 (PubMed:25514493). Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A (PubMed:25514493). Interacts with HDAC1 (PubMed:25514493). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850).DOMAIN The MH1 domain is required for DNA binding.DOMAIN The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import.PTM Phosphorylated by PDPK1.PTM Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.DISEASE SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.SIMILARITY Belongs to the dwarfin/SMAD family.UniProtQ134851EQUAL552EQUALReactome Database ID Release 758878153Database 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=8878153ReactomeR-HSA-88781531Reactome 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-HSA-8878153.1Reactome DB_ID: 88653931UniProt:Q13761 RUNX3RUNX3CBFA3PEBP2A3AML2RUNX3FUNCTION Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (By similarity). May be involved in the control of cellular proliferation and/or differentiation. In association with ZFHX3, upregulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing (By similarity).SUBUNIT Heterodimer with CBFB. RUNX3 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization (By similarity). Interacts with TLE1 and SUV39H1 (PubMed:9751710 and PubMed:16652147). The tyrosine phosphorylated form (via runt domain) interacts with SRC (via protein kinase domain)(PubMed:20100835). Interacts with FYN and LCK (PubMed:20100835). Interacts with FOXP3 (PubMed:17377532). Interacts with ZFHX3 (PubMed:20599712). Interacts with TBX21 (By similarity).TISSUE SPECIFICITY Expressed in gastric cancer tissues (at protein level).DOMAIN A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.PTM Phosphorylated on tyrosine residues by SRC. Phosphorylated by LCK and FYN.UniProtQ137611EQUAL415EQUALReactome DB_ID: 88781461RUNX3:p-2S-SMAD3:p-2S-SMAD3:SMAD4 [nucleoplasm]RUNX3:p-2S-SMAD3:p-2S-SMAD3:SMAD4Reactome DB_ID: 88781531Reactome DB_ID: 886539311EQUAL415EQUALReactome Database ID Release 758878146Database 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=8878146ReactomeR-HSA-88781461Reactome 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-HSA-8878146.1Reactome Database ID Release 758878143Database 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=8878143ReactomeR-HSA-88781432Reactome 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-HSA-8878143.210531362Pubmed1999Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoterHanai, JChen, L FKanno, TOhtani-Fujita, NKim, W YGuo, W HImamura, TIshidou, YFukuchi, MShi, M JStavnezer, JKawabata, MMiyazono, KIto, YJ. Biol. Chem. 274:31577-8216135801Pubmed2005RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMADChi, Xin-ZiYang, Jeung-OokLee, Kwang-YoulIto, KoseiSakakura, ChoheiLi, Qing-LinKim, Hye-RyunCha, Eun-JeungLee, Yong-HeeKaneda, AtsushiUshijima, ToshikazuKim, Wun-JaeIto, YoshiakiBae, Suk-ChulMol. Cell. Biol. 25:8097-107The complex of RUNX3, SMAD3 and SMAD4 binds the CDKN1A gene promoterThe complex of RUNX3, SMAD3 and SMAD4 binds the CDKN1A gene promoterThe CDKN1A (p21) gene promoter contains five putative RUNX3 binding sites. RUNX3 binds the CDKN1A promoter. The complex of SMAD4 and activated SMAD3, a known CDKN1A transcriptional activator, can bind to RUNX3 to cooperatively activate the CDKN1A gene transcription (Chi et al. 2005).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Reactome DB_ID: 88781461Reactome DB_ID: 37862561ENSEMBL:ENSG00000124762 CDKN1ACDKN1APIC1CIP1MDA6CDKN1WAF1CAP20SDI1ENSEMBLENSG00000124762Reactome DB_ID: 88781801RUNX3:p-2S-SMAD3:p-2S-SMAD3:SMAD4:CDKN1A gene [nucleoplasm]RUNX3:p-2S-SMAD3:p-2S-SMAD3:SMAD4:CDKN1A geneReactome DB_ID: 88781461Reactome DB_ID: 37862561Reactome Database ID Release 758878180Database 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=8878180ReactomeR-HSA-88781801Reactome 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-HSA-8878180.1Reactome Database ID Release 758878178Database 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=8878178ReactomeR-HSA-88781781Reactome 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-HSA-8878178.1CDKN1A gene expression is synergistically activated by RUNX3, SMAD3 and SMAD4CDKN1A gene expression is synergistically activated by RUNX3, SMAD3 and SMAD4RUNX3 binds the complex of SMAD4 and SMAD3, generated in response to TGF-beta (TGFB1) signaling. While the individual action of the SMAD3:SMAD4 complex or RUNX3 can induce 2-3-fold activation of CDKN1A transcription, the synergistic action of SMAD3, SMAD4 and RUNX3 induces 10-fold activation of CDKN1A transcription. Runx3 knockout mice exhibit decreased sensitivity to TGF-beta and develop gastric epithelial hyperplasia (Chi et al. 2005).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Reactome DB_ID: 37862561Reactome DB_ID: 1825851UniProt:P38936 CDKN1ACDKN1ACDKN1APIC1CIP1MDA6CDKN1WAF1CAP20SDI1FUNCTION May be involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739). Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest (PubMed:9106657).SUBUNIT Interacts with HDAC1; the interaction is prevented by competitive binding of C10orf90/FATS to HDAC1 facilitating acetylation and protein stabilization of CDKN1A/p21 (By similarity). Interacts with MKRN1 (PubMed:19536131). Interacts with PSMA3 (PubMed:11350925). Interacts with PCNA (PubMed:11595739, PubMed:18794347, PubMed:18703516, PubMed:8861913). Component of the ternary complex, cyclin D-CDK4-CDKN1A. Interacts (via its N-terminal domain) with CDK4; the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4 (PubMed:9106657). Binding to CDK2 leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair (PubMed:19445729). Interacts with PIM1 (PubMed:12431783). Interacts with STK11 and NUAK1 (PubMed:25329316). Interacts wih DTL (PubMed:23213251). Interacts with isoform 1 and isoform 2 of TRIM39 (PubMed:23213251).TISSUE SPECIFICITY Expressed in all adult tissues, with 5-fold lower levels observed in the brain.INDUCTION Activated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1.DOMAIN The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination.DOMAIN The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex.PTM Phosphorylation of Thr-145 by Akt or of Ser-146 by PKC impairs binding to PCNA. Phosphorylation at Ser-114 by GSK3-beta enhances ubiquitination by the DCX(DTL) complex. Phosphorylation of Thr-145 by PIM2 enhances CDKN1A stability and inhibits cell proliferation. Phosphorylation of Thr-145 by PIM1 results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. UV radiation-induced phosphorylation at Thr-80 by LKB1 and at Ser-146 by NUAK1 leads to its degradation.PTM Ubiquitinated by MKRN1; leading to polyubiquitination and 26S proteasome-dependent degradation. Ubiquitinated by the DCX(DTL) complex, also named CRL4(CDT2) complex, leading to its degradation during S phase or following UV irradiation. Ubiquitination by the DCX(DTL) complex is essential to control replication licensing and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Ubiquitination at Ser-2 leads to degradation by the proteasome pathway. Ubiquitinated by RNF114; leading to proteasomal degradation.PTM Acetylation leads to protein stability. Acetylated in vitro on Lys-141, Lys-154, Lys-161 and Lys-163. Deacetylation by HDAC1 is prevented by competitive binding of C10orf90/FATS to HDAC1 (By similarity).SIMILARITY Belongs to the CDI family.UniProtP389362EQUAL164EQUALReactome Database ID Release 758878186Database 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=8878186ReactomeR-HSA-88781863Reactome 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-HSA-8878186.3ACTIVATIONReactome Database ID Release 758878185Database 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=8878185ReactomeR-HSA-88781851Reactome 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-HSA-8878185.1Reactome DB_ID: 8878180RUNX3 binds ZFHX3RUNX3 binds ZFHX3In response to TGF-beta (TGFB1) signaling, RUNX3 binds to the homeobox transcription factor and tumor suppressor ZFHX3 (ATBF1). The exact mechanism and regulation of RUNX3 and ATBF1 binding is not known (Mabuchi et al. 2010).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Reactome DB_ID: 88780841UniProt:Q15911 ZFHX3ZFHX3ATBF1ZFHX3FUNCTION Transcriptional regulator which can act as an activator or a repressor. Inhibits the enhancer element of the AFP gene by binding to its AT-rich core sequence. In concert with SMAD-dependent TGF-beta signaling can repress the transcription of AFP via its interaction with SMAD2/3 (PubMed:25105025). Regulates the circadian locomotor rhythms via transcriptional activation of neuropeptidergic genes which are essential for intercellular synchrony and rhythm amplitude in the suprachiasmatic nucleus (SCN) of the brain (By similarity). Regulator of myoblasts differentiation through the binding to the AT-rich sequence of MYF6 promoter and promoter repression (PubMed:11312261). Down-regulates the MUC5AC promoter in gastric cancer (PubMed:17330845). In association with RUNX3, upregulates CDKN1A promoter activity following TGF-beta stimulation (PubMed:20599712). Inhibits estrogen receptor (ESR1) function by selectively competing with coactivator NCOA3 for binding to ESR1 in ESR1-positive breast cancer cells (PubMed:20720010).SUBUNIT Interacts with FNBP3 (By similarity). Interacts with ALKBH4 and PIAS3. Interacts with ESR1. Interacts with RUNX3. Interacts with TRIM25. Interacts with SMAD2 and SMAD3.TISSUE SPECIFICITY Not found in normal gastric mucosa but found in gastric carcinoma cells (at protein level). Expression is higher in ER-positive breast tumors than ER-negative breast tumors (at protein level).PTM Phosphorylation decreases its sensitivity to calpain-mediated proteolysis.PTM Adult brain-derived ZFHX3 is sensitive, but embryonic brain-derived ZFHX3 is resistant to calpain 1-mediated proteolysis.PTM Ubiquitinated, leading to its proteasomal degradation.PTM Nuclear localization is essential for its sumoylation.POLYMORPHISM Genetic variations in ZFHX3 are associated with atrial fibrillation and ischemic stroke in individuals of European ancestry.UniProtQ159111EQUAL3703EQUALReactome DB_ID: 886539311EQUAL415EQUALReactome DB_ID: 88781201RUNX3:ZFHX3 [nucleoplasm]RUNX3:ZFHX3Reactome DB_ID: 887808411EQUAL3703EQUALReactome DB_ID: 886539311EQUAL415EQUALReactome Database ID Release 758878120Database 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=8878120ReactomeR-HSA-88781201Reactome 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-HSA-8878120.1Reactome Database ID Release 758878117Database 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=8878117ReactomeR-HSA-88781174Reactome 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-HSA-8878117.420599712Pubmed2010Tumor suppressor, AT motif binding factor 1 (ATBF1), translocates to the nucleus with runt domain transcription factor 3 (RUNX3) in response to TGF-beta signal transductionMabuchi, MotoshiKataoka, HiromiMiura, YutakaKim, Tae-SunKawaguchi, MakotoEbi, MasahideTanaka, MamoruMori, YoshinoriKubota, EijiMizushima, TakashiShimura, TakayaMizoshita, TsutomuTanida, SatoshiKamiya, TakeshiAsai, KJoh, TakashiBiochem. Biophys. Res. Commun. 398:321-5ACTIVATIONReactome Database ID Release 758878110Database 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=8878110ReactomeR-HSA-88781101Reactome 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-HSA-8878110.1Reactome DB_ID: 170852extracellular regionGO0005576Dimeric TGFB1 [extracellular region]Dimeric TGFB1Dimeric TGF-beta 1Reactome DB_ID: 1708382UniProt:P01137 TGFB1TGFB1TGFB1TGFBFUNCTION Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.FUNCTION Transforming growth factor beta-1: Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (By similarity). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (PubMed:29109152). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:2022183, PubMed:8617200, PubMed:8939931, PubMed:19750484, PubMed:22278742, PubMed:19651619). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (PubMed:20207738). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (By similarity). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (By similarity). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (By similarity). At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292, PubMed:29483653, PubMed:30696809). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292, PubMed:30696809).SUBUNIT Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling. The HTRA protease activity is required for this inhibition (By similarity). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling (By similarity). Interacts with CD109, DPT and ASPN (PubMed:9895299, PubMed:16754747, PubMed:17827158). Latency-associated peptide: Homodimer; disulfide-linked (PubMed:28117447, PubMed:29109152). Latency-associated peptide: Interacts with Transforming growth factor beta-1 (TGF-beta-1) chain; interaction is non-covalent and maintains (TGF-beta-1) in a latent state; each Latency-associated peptide (LAP) monomer interacts with TGF-beta-1 in the other monomer (PubMed:29109152). Latency-associated peptide: Interacts with LTBP1; leading to regulate activation of TGF-beta-1 (PubMed:2022183, PubMed:8617200, PubMed:8939931). Latency-associated peptide: Interacts with LRRC32/GARP; leading to regulate activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:22278742, PubMed:19651619). Interacts with LRRC33/NRROS; leading to regulate activation of TGF-beta-1 in macrophages and microglia (Probable). Latency-associated peptide: Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1 (PubMed:22278742, PubMed:28117447). Latency-associated peptide: Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction (By similarity). Latency-associated peptide: Interacts with HSP90AB1; inhibits latent TGFB1 activation (PubMed:20599762). Transforming growth factor beta-1: Homodimer; disulfide-linked (PubMed:20207738, PubMed:25209176, PubMed:28117447, PubMed:29109152). Transforming growth factor beta-1: Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (PubMed:20207738).TISSUE SPECIFICITY Highly expressed in bone (PubMed:11746498, PubMed:17827158). Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA) (PubMed:11746498, PubMed:17827158). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage (PubMed:17827158).PTM Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive.POLYMORPHISM In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.MISCELLANEOUS TGF-beta-1 is inactivated by fresolimumab (also named GC1008), a monoclonal-neutralizing antibody.SIMILARITY Belongs to the TGF-beta family.UniProtP01137279EQUAL390EQUALReactome Database ID Release 75170852Database 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=170852ReactomeR-HSA-1708521Reactome 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-HSA-170852.1CDKN1A (p21) gene expression is positively regulated by RUNX3 and ZFHX3CDKN1A (p21) gene expression is positively regulated by RUNX3 and ZFHX3Transcription of the CDKN1A (p21) gene is synergistically stimulated by RUNX3 and ZFHX3 (ATBF1), presumably through formation of the complex between RUNX3 and ZFHX3. RUNX3 and ZFHX3 can also stimulate CDKN1A transcription independently of one another, albeit to a lower level than when they act in tandem (Mabuchi et al. 2010).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Reactome DB_ID: 37862561Reactome DB_ID: 18258512EQUAL164EQUALReactome Database ID Release 758878130Database 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=8878130ReactomeR-HSA-88781303Reactome 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-HSA-8878130.3ACTIVATIONReactome Database ID Release 758878128Database 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=8878128ReactomeR-HSA-88781281Reactome 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-HSA-8878128.1Reactome DB_ID: 8878120RUNX3 binds TP53RUNX3 binds TP53RUNX3 can bind to TP53 (p53). The interaction involves the C-termini of both RUNX3 and TP53. RUNX3 may act as a TP53 co-factor, stimulating TP53-mediated transcription of target genes, including CDKN1A (p21). RUNX3 may also interact with phosphorylated ATM kinase in response to DNA damage and facilitate ATM-mediated phosphorylation and stabilization of TP53 (Yamada et al. 2010).Authored: Orlic-Milacic, Marija, 2016-12-12Reviewed: Ito, Yoshiaki, 2017-01-31Reviewed: Chuang, Linda Shyue Huey, 2017-01-31Edited: Orlic-Milacic, Marija, 2017-01-31Reactome DB_ID: 32091941TP53 Tetramer [nucleoplasm]TP53 TetramerReactome DB_ID: 694884UniProt:P04637 TP53TP53TP53P53FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).SUBUNIT Forms homodimers and homotetramers (PubMed:19011621). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, BANP, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3 (PubMed:17332504). Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus) (PubMed:17145718). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53 (PubMed:22522597). Interacts with AFG1L; mediates mitochondrial translocation of TP53 (PubMed:27323408). Interacts with UBD (PubMed:25422469). Interacts with TAF6 isoform 1 and isoform 4 (PubMed:20096117). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Interacts with PRMT5 in response to DNA damage; the interaction is STRAP dependent (PubMed:19011621). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (PubMed:12524540). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (PubMed:28842590). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (PubMed:17954561).SUBUNIT (Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation.TISSUE SPECIFICITY Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.INDUCTION Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.DOMAIN The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.PTM Acetylated. Acetylation of Lys-382 by CREBBP enhances transcriptional activity. Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner.PTM Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated on Ser-15 upon ultraviolet irradiation; which is enhanced by interaction with BANP. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1 (PubMed:21317932). It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (PubMed:28842590).PTM Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.PTM May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.PTM Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation (PubMed:10722742, PubMed:12810724, PubMed:15340061, PubMed:17170702, PubMed:19880522). Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:10722742, PubMed:12810724, PubMed:20173098). Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation (PubMed:19536131). Deubiquitinated by USP10, leading to its stabilization (PubMed:20096447). Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation (PubMed:19556538). Ubiquitination by TOPORS induces degradation (PubMed:19473992). Deubiquitination by USP7, leading to stabilization (PubMed:15053880). Isoform 4 is monoubiquitinated in an MDM2-independent manner (PubMed:15340061). Ubiquitinated by COP1, which leads to proteasomal degradation (PubMed:19837670). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity).PTM Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation (PubMed:15525938, PubMed:16415881). Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity (PubMed:17108971). Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370 (PubMed:17108971). Dimethylated at Lys-373 by EHMT1 and EHMT2 (PubMed:20118233). Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity (PubMed:17707234). Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20 (PubMed:22864287). Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (PubMed:17805299). Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (PubMed:19011621).PTM Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.DISEASE TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.SIMILARITY Belongs to the p53 family.UniProtP046371EQUAL393EQUALReactome Database ID Release 753209194Database 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=3209194ReactomeR-HSA-32091941Reactome 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-HSA-3209194.1Reactome DB_ID: 886539311EQUAL415EQUALReactome DB_ID: 89521231RUNX3:TP53 tetramer [nucleoplasm]RUNX3:TP53 tetramerReactome DB_ID: 32091941Reactome DB_ID: 886539311EQUAL415EQUALReactome Database ID Release 758952123Database 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=8952123ReactomeR-HSA-89521231Reactome 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-HSA-8952123.1Reactome Database ID Release 758952128Database 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=8952128ReactomeR-HSA-89521282Reactome 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-HSA-8952128.220353948Pubmed2010RUNX3 modulates DNA damage-mediated phosphorylation of tumor suppressor p53 at Ser-15 and acts as a co-activator for p53Yamada, ChizuOzaki, ToshinoriAndo, KSuenaga, YusukeInoue, Ken-ichiIto, YoshiakiOkoshi, RintaroKageyama, HajimeKimura, HidekiMiyazaki, MasaruNakagawara, AkiraJ. Biol. Chem. 285:16693-703Reactome Database ID Release 758941855Database 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=8941855ReactomeR-HSA-89418551Reactome 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-HSA-8941855.1