Reactome | TP53 Regulates Transcription of Cell Death Genes

TP53 Regulates Transcription of Cell Death Genes

Stable Identifier

R-HSA-5633008

Type

Pathway

Species

Homo sapiens

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TP53 Regulates Transcription of Cell Death Genes

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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.
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).

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).

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).

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.

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.

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).

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.

Literature References

PubMed ID	Title	Journal	Year
11684014	ASPP proteins specifically stimulate the apoptotic function of p53 Samuels-Lev, Y, O'Connor, DJ, Bergamaschi, D, Trigiante, G, Hsieh, JK, Zhong, S, Campargue, I, Naumovski, L, Crook, T, Lu, X	Mol. Cell	2001
24739573	Unravelling mechanisms of p53-mediated tumour suppression Bieging, KT, Mello, SS, Attardi, LD	Nat. Rev. Cancer	2014
7566179	Induction of the growth inhibitor IGF-binding protein 3 by p53 Buckbinder, L, Talbott, R, Velasco-Miguel, S, Takenaka, I, Faha, B, Seizinger, BR, Kley, N	Nature	1995
17349958	DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage Taira, N, Nihira, K, Yamaguchi, T, Miki, Y, Yoshida, K	Mol. Cell	2007
26122615	p53 in survival, death and metabolic health: a lifeguard with a licence to kill Kruiswijk, F, Labuschagne, CF, Vousden, KH	Nat. Rev. Mol. Cell Biol.	2015
11278253	Direct transcriptional activation of human caspase-1 by tumor suppressor p53 Gupta, S, Radha, V, Furukawa, Y, Swarup, G	J. Biol. Chem.	2001
23703390	Caspase-1 is a novel target of p63 in tumor suppression Celardo, I, Grespi, F, Antonov, A, Bernassola, F, Garabadgiu, AV, Melino, G, Amelio, I	Cell Death Dis	2013
12606722	The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase Passer, BJ, Nancy-Portebois, V, Amzallag, N, Prieur, S, Cans, C, Roborel de Climens, A, Fiucci, G, Bouvard, V, Tuynder, M, Susini, L, Morchoisne, S, Crible, V, Lespagnol, A, Dausset, J, Oren, M, Amson, R, Telerman, A	Proc. Natl. Acad. Sci. U.S.A.	2003
10777207	Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site Takimoto, R, el-Deiry, WS	Oncogene	2000
14614825	Perp is a mediator of p53-dependent apoptosis in diverse cell types Ihrie, RA, Reczek, E, Horner, JS, Khachatrian, L, Sage, J, Jacks, T, Attardi, LD	Curr. Biol.	2003
10973264	Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis Lin, Y, Ma, W, Benchimol, S	Nat. Genet.	2000
16135520	Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin Jain, N, Gupta, S, Sudhakar, Ch, Radha, V, Swarup, G	J. Biol. Chem.	2005
15577913	The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells Phan, RT, Dalla-Favera, R	Nature	2004
15273740	AMID is a p53-inducible gene downregulated in tumors Wu, M, Xu, LG, Su, T, Tian, Y, Zhai, Z, Shu, HB	Oncogene	2004
16249378	BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma Margalit, O, Amram, H, Amariglio, N, Simon, AJ, Shaklai, S, Granot, G, Minsky, N, Shimoni, A, Harmelin, A, Givol, D, Shohat, M, Oren, M, Rechavi, G	Blood	2006
10807576	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	2000
22766503	iASPPsv antagonizes apoptosis induced by chemotherapeutic agents in MCF-7 cells and mouse thymocytes Wang, L, Xing, H, Tian, Z, Peng, L, Li, Y, Tang, K, Rao, Q, Wang, M, Wang, J	Biochem. Biophys. Res. Commun.	2012
23365256	ASPP1/2 regulate p53-dependent death of retinal ganglion cells through PUMA and Fas/CD95 activation in vivo Wilson, AM, Morquette, B, Abdouh, M, Unsain, N, Barker, PA, Feinstein, E, Bernier, G, Di Polo, A	J. Neurosci.	2013
11559530	APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis Robles, AI, Bemmels, NA, Foraker, AB, Harris, CC	Cancer Res.	2001
14688482	Caspase 10 levels are increased following DNA damage in a p53-dependent manner Rikhof, B, Corn, PG, El-Deiry, WS	Cancer Biol. Ther.	2003
12089322	Apoptotic threshold is lowered by p53 transactivation of caspase-6 MacLachlan, TK, El-Deiry, WS	Proc. Natl. Acad. Sci. U.S.A.	2002
15607964	Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth Fei, P, Wang, W, Kim, SH, Wang, S, Burns, TF, Sax, JK, Buzzai, M, Dicker, DT, McKenna, WG, Bernhard, EJ, El-Deiry, WS	Cancer Cell	2004
15289308	p53 upregulates death receptor 4 expression through an intronic p53 binding site Liu, X, Yue, P, Khuri, FR, Sun, SY	Cancer Res.	2004
17284521	Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death Brough, D, Rothwell, NJ	J Cell Sci	2007
15735003	p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway Park, WR, Nakamura, Y	Cancer Res.	2005
12851404	TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity Tomasini, R, Samir, AA, Carrier, A, Isnardon, D, Cecchinelli, B, Soddu, S, Malissen, B, Dagorn, JC, Iovanna, JL, Dusetti, NJ	J. Biol. Chem.	2003
17442733	p53-dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion Zhang, AH, Rao, JN, Zou, T, Liu, L, Marasa, BS, Xiao, L, Chen, J, Turner, DJ, Wang, JY	Am. J. Physiol., Cell Physiol.	2007
20353938	Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer Ingermann, AR, Yang, YF, Han, J, Mikami, A, Garza, AE, Mohanraj, L, Fan, L, Idowu, M, Ware, JL, Kim, HS, Lee, DY, Oh, Y	J. Biol. Chem.	2010
18676979	Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax Patel, S, George, R, Autore, F, Fraternali, F, Ladbury, JE, Nikolova, PV	Nucleic Acids Res.	2008
14729977	ASPP1 and ASPP2: common activators of p53 family members Bergamaschi, D, Samuels, Y, Jin, B, Duraisingham, S, Crook, T, Lu, X	Mol. Cell. Biol.	2004
18431400	Transcriptional control of human p53-regulated genes Riley, T, Sontag, E, Chen, P, Levine, A	Nat. Rev. Mol. Cell Biol.	2008
19549844	BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma Saito, M, Novak, U, Piovan, E, Basso, K, Sumazin, P, Schneider, C, Crespo, M, Shen, Q, Bhagat, G, Califano, A, Chadburn, A, Pasqualucci, L, Dalla-Favera, R	Proc. Natl. Acad. Sci. U.S.A.	2009
15126337	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	2004
12402042	BID regulation by p53 contributes to chemosensitivity Sax, JK, Fei, P, Murphy, ME, Bernhard, E, Korsmeyer, SJ, El-Deiry, WS	Nat. Cell Biol.	2002
11463392	PUMA, a novel proapoptotic gene, is induced by p53 Nakano, K, Vousden, KH	Mol Cell	2001
10733530	PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family Attardi, LD, Reczek, EE, Cosmas, C, Demicco, EG, McCurrach, ME, Lowe, SW, Jacks, T	Genes Dev.	2000
19615968	Active transcription of the human FAS/CD95/TNFRSF6 gene involves the p53 family Schilling, T, Schleithoff, ES, Kairat, A, Melino, G, Stremmel, W, Oren, M, Krammer, PH, Müller, M	Biochem. Biophys. Res. Commun.	2009
11511362	p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis Okamura, S, Arakawa, H, Tanaka, T, Nakanishi, H, Ng, CC, Taya, Y, Monden, M, Nakamura, Y	Mol. Cell	2001
15797384	Perp is a p63-regulated gene essential for epithelial integrity Ihrie, RA, Marques, MR, Nguyen, BT, Horner, JS, Papazoglu, C, Bronson, RT, Mills, AA, Attardi, LD	Cell	2005
11919562	A polymorphic microsatellite that mediates induction of PIG3 by p53 Contente, A, Dittmer, A, Koch, MC, Roth, J, Dobbelstein, M	Nat. Genet.	2002
15580302	Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis Sadasivam, S, Gupta, S, Radha, V, Batta, K, Kundu, TK, Swarup, G	Oncogene	2005
16140933	Identification of novel p53 target genes in ionizing radiation response Jen, KY, Cheung, VG	Cancer Res.	2005
19040420	P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma Davies, L, Gray, D, Spiller, D, White, MR, Damato, B, Grierson, I, Paraoan, L	J. Cell. Mol. Med.	2009
16230375	Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity Liu, X, Yue, P, Khuri, FR, Sun, SY	Cancer Res.	2005
11054413	Bcl-G, a novel pro-apoptotic member of the Bcl-2 family Guo, B, Godzik, A, Reed, JC	J. Biol. Chem.	2001
7834749	Tumor suppressor p53 is a direct transcriptional activator of the human bax gene Miyashita, T, Reed, JC	Cell	1995
9326928	KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene Wu, GS, Burns, TF, McDonald, ER, Jiang, W, Meng, R, Krantz, ID, Kao, G, Gan, DD, Zhou, JY, Muschel, R, Hamilton, SR, Spinner, NB, Markowitz, S, Wu, G, el-Deiry, WS	Nat. Genet.	1997
15377670	NDRG1 is necessary for p53-dependent apoptosis Stein, S, Thomas, EK, Herzog, B, Westfall, MD, Rocheleau, JV, Jackson, RS, Wang, M, Liang, P	J. Biol. Chem.	2004
23059823	Bcl-2 family member Bcl-G is not a proapoptotic protein Giam, M, Okamoto, T, Mintern, JD, Strasser, A, Bouillet, P	Cell Death Dis	2012
11382926	Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene Guan, B, Yue, P, Clayman, GL, Sun, SY	J. Cell. Physiol.	2001
18719709	A complex barcode underlies the heterogeneous response of p53 to stress Murray-Zmijewski, F, Slee, EA, Lu, X	Nat. Rev. Mol. Cell Biol.	2008
14623878	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, C, Ruiz-Ruiz, C, Rodríguez, A, Ortiz-Ferrón, G, Redondo, JM, López-Rivas, A	J. Biol. Chem.	2004