Regulation of TP53 activity through association with cofactors (Homo sapiens)

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1, 3, 6, 11, 15...14, 1194911, 127, 12875, 83, 86, 10541, 72, 99, 13013, 21, 35, 1055, 11114, 1195, 1111, 61111cytosolnucleoplasmZNF385APPP1R13Lp-S15,S20-TP53 Me2K-370,382-TP53 TP73 ZNF385A Gene (p-S15,S20-TP53,TP63,TP73):PPP1R13LRegulation of TP53Activity throughPhosphorylationp-S15,S20-TP53 p-T308,S473-AKT1 p-T309,S474-AKT2 PHF20TP53 p-S15,S20-TP53 TP53:BANPTP53 TetramerZNF385A GeneTP63 TP53BP2 p-S15,S20-TP53,TP63,TP73p-S15,S20-TP53Tetramer:POU4F2p-S15,S20-TP53 p-S291-PHF20POU4F1 p-S15,S20-TP53Tetramer:ZNF385AMe2-K370,K382-TP53TetramerMe2K-370,382-TP53 ATPp-S15,S20-TP53 PPP1R13B p-S15,S20-TP53Tetramer:ZNF385AGenep-S15,S20-TP53TetramerBANP TP73 BANPPHF20:Me2-K370,K382-TP53 Tetramerp-S15,S20-TP53 PHF20 TP63 POU4F2 PPP1R13B,TP53BP2TP63 p-S15,S20-TP53 p-S291-PHF20TP53BP2 p-S15,S20-TP53 PPP1R13B TP53 ZNF385A POU4F1(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)PPP1R13L Active AKTp-S15,S20-TP53Tetramer:POU4F1TP53 RegulatesTranscription ofCell Cycle GenesTP53 RegulatesTranscription ofCell Death GenesADPTP73 POU4F2p-T305,S472-AKT3 127, 1287, 12, 17-19, 24...52, 8, 19, 20, 32...4, 7, 9, 10, 22...6141, 994921, 105111


Description

Association of TP53 (p53) with various transcriptional co-factors can promote, inhibit or provide specificity towards either transcription of cell cycle arrest genes or transcription of cell death genes. Binding of the zinc finger protein ZNF385A (HZF), which is a transcriptional target of TP53, stimulates transcription of cell cycle arrest genes, such as CDKN1A (Das et al. 2007). Binding of POU4F1 (BRN3A) to TP53 also stimulates transcription of cell cycle arrest genes while inhibiting transcription of pro-apoptotic genes (Budhram-Mahadeo et al. 1999, Hudson et al. 2005).

Binding of ASPP family proteins PPP1R13B (ASPP1) or TP53BP2 (ASPP2) to TP53 stimulates transcription of pro-apoptotic TP53 targets (Samuels-Lev et al. 2001, Bergamaschi et al. 2004). Binding of the ASPP family member PPP1R13L (iASSP) inhibits TP53-mediated activation of pro-apoptotic genes probably by interfering with binding of stimulatory ASPPs to TP53 (Bergamaschi et al. 2003). Transcription of pro-apoptotic genes is also stimulated by binding of TP53 to POU4F2 (BRN3B) (Budrham-Mahadeo et al. 2006, Budhram-Mahadeo et al. 2014) or to hCAS/CSE1L (Tanaka et al. 2007).<p>Binding of co-factors to TP53 can also affect protein stability. For example, PHF20 binds to TP53 dimethylated on lysine residues K370 and K382 by unidentified protein lysine methyltransferase(s) and interferes with MDM2 binding, resulting in prolonged TP53 half-life (Cui et al. 2012). Long noncoding RNAs can contribute to p53-dependent transcriptional responses (Huarte et al. 2010). For a general review on this topic, see Espinosa 2008, Beckerman and Prives 2010, Murray-Zmijewski et al. 2008, An et al. 2004 and Barsotti and Prives 2010. View original pathway at:Reactome.</div>

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Pathway is converted from Reactome ID: 6804759
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Reactome version: 61
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Reactome Author: Orlic-Milacic, Marija

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  1. Patel S, George R, Autore F, Fraternali F, Ladbury JE, Nikolova PV.; ''Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax.''; PubMed Europe PMC Scholia
  2. Peeper DS, Shvarts A, Brummelkamp T, Douma S, Koh EY, Daley GQ, Bernards R.; ''A functional screen identifies hDRIL1 as an oncogene that rescues RAS-induced senescence.''; PubMed Europe PMC Scholia
  3. Mauxion F, Faux C, Séraphin B.; ''The BTG2 protein is a general activator of mRNA deadenylation.''; PubMed Europe PMC Scholia
  4. Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y.; ''p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis.''; PubMed Europe PMC Scholia
  5. Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ.; ''Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.''; PubMed Europe PMC Scholia
  6. Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, Fujii S, Arlinghaus RB, Czerniak BA, Sen S.; ''Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53.''; PubMed Europe PMC Scholia
  7. Guo B, Godzik A, Reed JC.; ''Bcl-G, a novel pro-apoptotic member of the Bcl-2 family.''; PubMed Europe PMC Scholia
  8. Xie S, Wu H, Wang Q, Cogswell JP, Husain I, Conn C, Stambrook P, Jhanwar-Uniyal M, Dai W.; ''Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway.''; PubMed Europe PMC Scholia
  9. Lin Y, Ma W, Benchimol S.; ''Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis.''; PubMed Europe PMC Scholia
  10. Riley T, Sontag E, Chen P, Levine A.; ''Transcriptional control of human p53-regulated genes.''; PubMed Europe PMC Scholia
  11. Kruiswijk F, Labuschagne CF, Vousden KH.; ''p53 in survival, death and metabolic health: a lifeguard with a licence to kill.''; PubMed Europe PMC Scholia
  12. Lakin ND, Hann BC, Jackson SP.; ''The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53.''; PubMed Europe PMC Scholia
  13. Park WR, Nakamura Y.; ''p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway.''; PubMed Europe PMC Scholia
  14. Kaul R, Mukherjee S, Ahmed F, Bhat MK, Chhipa R, Galande S, Chattopadhyay S.; ''Direct interaction with and activation of p53 by SMAR1 retards cell-cycle progression at G2/M phase and delays tumor growth in mice.''; PubMed Europe PMC Scholia
  15. Sinha S, Malonia SK, Mittal SP, Singh K, Kadreppa S, Kamat R, Mukhopadhyaya R, Pal JK, Chattopadhyay S.; ''Coordinated regulation of p53 apoptotic targets BAX and PUMA by SMAR1 through an identical MAR element.''; PubMed Europe PMC Scholia
  16. Brough D, Rothwell NJ.; ''Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death.''; PubMed Europe PMC Scholia
  17. Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW.; ''DNA damage-induced activation of p53 by the checkpoint kinase Chk2.''; PubMed Europe PMC Scholia
  18. Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS.; ''Characterisation of the interaction between PCNA and Gadd45.''; PubMed Europe PMC Scholia
  19. Bahassi el M, Hennigan RF, Myer DL, Stambrook PJ.; ''Cdc25C phosphorylation on serine 191 by Plk3 promotes its nuclear translocation.''; PubMed Europe PMC Scholia
  20. Xie S, Wang Q, Wu H, Cogswell J, Lu L, Jhanwar-Uniyal M, Dai W.; ''Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3.''; PubMed Europe PMC Scholia
  21. Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW, Jacks T.; ''PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family.''; PubMed Europe PMC Scholia
  22. Hou X, Liu JE, Liu W, Liu CY, Liu ZY, Sun ZY.; ''A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation.''; PubMed Europe PMC Scholia
  23. Lee JH, Kim HS, Lee SJ, Kim KT.; ''Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death.''; PubMed Europe PMC Scholia
  24. Hofmann TG, Möller A, Sirma H, Zentgraf H, Taya Y, Dröge W, Will H, Schmitz ML.; ''Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2.''; PubMed Europe PMC Scholia
  25. Bergamaschi D, Samuels Y, Jin B, Duraisingham S, Crook T, Lu X.; ''ASPP1 and ASPP2: common activators of p53 family members.''; PubMed Europe PMC Scholia
  26. Shieh SY, Ahn J, Tamai K, Taya Y, Prives C.; ''The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites.''; PubMed Europe PMC Scholia
  27. Rouault JP, Prévôt D, Berthet C, Birot AM, Billaud M, Magaud JP, Corbo L.; ''Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex.''; PubMed Europe PMC Scholia
  28. Lee JH, Jeong MW, Kim W, Choi YH, Kim KT.; ''Cooperative roles of c-Abl and Cdk5 in regulation of p53 in response to oxidative stress.''; PubMed Europe PMC Scholia
  29. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N.; ''Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.''; PubMed Europe PMC Scholia
  30. Contente A, Dittmer A, Koch MC, Roth J, Dobbelstein M.; ''A polymorphic microsatellite that mediates induction of PIG3 by p53.''; PubMed Europe PMC Scholia
  31. Krause A, Hoffmann I.; ''Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4 triggers centriole duplication.''; PubMed Europe PMC Scholia
  32. Jen KY, Cheung VG.; ''Identification of novel p53 target genes in ionizing radiation response.''; PubMed Europe PMC Scholia
  33. Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ.; ''TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity.''; PubMed Europe PMC Scholia
  34. Rozenfeld-Granot G, Krishnamurthy J, Kannan K, Toren A, Amariglio N, Givol D, Rechavi G.; ''A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1.''; PubMed Europe PMC Scholia
  35. Suzuki M, Okuyama S, Okamoto S, Shirasuna K, Nakajima T, Hachiya T, Nojima H, Sekiya S, Oda K.; ''A novel E2F binding protein with Myc-type HLH motif stimulates E2F-dependent transcription by forming a heterodimer.''; PubMed Europe PMC Scholia
  36. Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y, Lu H.; ''A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1.''; PubMed Europe PMC Scholia
  37. Ruiz de Almodóvar C, Ruiz-Ruiz C, Rodríguez A, Ortiz-Ferrón G, Redondo JM, López-Rivas A.; ''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.''; PubMed Europe PMC Scholia
  38. Bergamaschi D, Samuels Y, O'Neil NJ, Trigiante G, Crook T, Hsieh JK, O'Connor DJ, Zhong S, Campargue I, Tomlinson ML, Kuwabara PE, Lu X.; ''iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human.''; PubMed Europe PMC Scholia
  39. Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K.; ''DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage.''; PubMed Europe PMC Scholia
  40. Gully CP, Velazquez-Torres G, Shin JH, Fuentes-Mattei E, Wang E, Carlock C, Chen J, Rothenberg D, Adams HP, Choi HH, Guma S, Phan L, Chou PC, Su CH, Zhang F, Chen JS, Yang TY, Yeung SC, Lee MH.; ''Aurora B kinase phosphorylates and instigates degradation of p53.''; PubMed Europe PMC Scholia
  41. Ma K, Araki K, Ichwan SJ, Suganuma T, Tamamori-Adachi M, Ikeda MA.; ''E2FBP1/DRIL1, an AT-rich interaction domain-family transcription factor, is regulated by p53.''; PubMed Europe PMC Scholia
  42. MacLachlan TK, El-Deiry WS.; ''Apoptotic threshold is lowered by p53 transactivation of caspase-6.''; PubMed Europe PMC Scholia
  43. Wang L, Xing H, Tian Z, Peng L, Li Y, Tang K, Rao Q, Wang M, Wang J.; ''iASPPsv antagonizes apoptosis induced by chemotherapeutic agents in MCF-7 cells and mouse thymocytes.''; PubMed Europe PMC Scholia
  44. Spengler D, Villalba M, Hoffmann A, Pantaloni C, Houssami S, Bockaert J, Journot L.; ''Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.''; PubMed Europe PMC Scholia
  45. Ingermann AR, Yang YF, Han J, Mikami A, Garza AE, Mohanraj L, Fan L, Idowu M, Ware JL, Kim HS, Lee DY, Oh Y.; ''Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer.''; PubMed Europe PMC Scholia
  46. Duriez C, Falette N, Audoynaud C, Moyret-Lalle C, Bensaad K, Courtois S, Wang Q, Soussi T, Puisieux A.; ''The human BTG2/TIS21/PC3 gene: genomic structure, transcriptional regulation and evaluation as a candidate tumor suppressor gene.''; PubMed Europe PMC Scholia
  47. Carvajal LA, Hamard PJ, Tonnessen C, Manfredi JJ.; ''E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression.''; PubMed Europe PMC Scholia
  48. Zhang AH, Rao JN, Zou T, Liu L, Marasa BS, Xiao L, Chen J, Turner DJ, Wang JY.; ''p53-dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion.''; PubMed Europe PMC Scholia
  49. Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT.; ''A role for ATR in the DNA damage-induced phosphorylation of p53.''; PubMed Europe PMC Scholia
  50. Abe Y, Matsumoto S, Wei S, Nezu K, Miyoshi A, Kito K, Ueda N, Shigemoto K, Hitsumoto Y, Nikawa J, Enomoto Y.; ''Cloning and characterization of a p53-related protein kinase expressed in interleukin-2-activated cytotoxic T-cells, epithelial tumor cell lines, and the testes.''; PubMed Europe PMC Scholia
  51. Lestari W, Ichwan SJ, Otsu M, Yamada S, Iseki S, Shimizu S, Ikeda MA.; ''Cooperation between ARID3A and p53 in the transcriptional activation of p21WAF1 in response to DNA damage.''; PubMed Europe PMC Scholia
  52. Rouault JP, Falette N, Guéhenneux F, Guillot C, Rimokh R, Wang Q, Berthet C, Moyret-Lalle C, Savatier P, Pain B, Shaw P, Berger R, Samarut J, Magaud JP, Ozturk M, Samarut C, Puisieux A.; ''Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway.''; PubMed Europe PMC Scholia
  53. Beckerman R, Prives C.; ''Transcriptional regulation by p53.''; PubMed Europe PMC Scholia
  54. Pavithra L, Mukherjee S, Sreenath K, Kar S, Sakaguchi K, Roy S, Chattopadhyay S.; ''SMAR1 forms a ternary complex with p53-MDM2 and negatively regulates p53-mediated transcription.''; PubMed Europe PMC Scholia
  55. Bieging KT, Mello SS, Attardi LD.; ''Unravelling mechanisms of p53-mediated tumour suppression.''; PubMed Europe PMC Scholia
  56. Keller DM, Lu H.; ''p53 serine 392 phosphorylation increases after UV through induction of the assembly of the CK2.hSPT16.SSRP1 complex.''; PubMed Europe PMC Scholia
  57. Samuels-Lev Y, O'Connor DJ, Bergamaschi D, Trigiante G, Hsieh JK, Zhong S, Campargue I, Naumovski L, Crook T, Lu X.; ''ASPP proteins specifically stimulate the apoptotic function of p53.''; PubMed Europe PMC Scholia
  58. Zhu J, Chen X.; ''MCG10, a novel p53 target gene that encodes a KH domain RNA-binding protein, is capable of inducing apoptosis and cell cycle arrest in G(2)-M.''; PubMed Europe PMC Scholia
  59. Ihrie RA, Marques MR, Nguyen BT, Horner JS, Papazoglu C, Bronson RT, Mills AA, Attardi LD.; ''Perp is a p63-regulated gene essential for epithelial integrity.''; PubMed Europe PMC Scholia
  60. Cai Y, Qiu S, Gao X, Gu SZ, Liu ZJ.; ''iASPP inhibits p53-independent apoptosis by inhibiting transcriptional activity of p63/p73 on promoters of proapoptotic genes.''; PubMed Europe PMC Scholia
  61. Sadasivam S, Gupta S, Radha V, Batta K, Kundu TK, Swarup G.; ''Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis.''; PubMed Europe PMC Scholia
  62. Burns TF, Fei P, Scata KA, Dicker DT, El-Deiry WS.; ''Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells.''; PubMed Europe PMC Scholia
  63. Scoumanne A, Cho SJ, Zhang J, Chen X.; ''The cyclin-dependent kinase inhibitor p21 is regulated by RNA-binding protein PCBP4 via mRNA stability.''; PubMed Europe PMC Scholia
  64. Samuel T, Weber HO, Rauch P, Verdoodt B, Eppel JT, McShea A, Hermeking H, Funk JO.; ''The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax.''; PubMed Europe PMC Scholia
  65. Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K.; ''ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage.''; PubMed Europe PMC Scholia
  66. Chehab NH, Malikzay A, Appel M, Halazonetis TD.; ''Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.''; PubMed Europe PMC Scholia
  67. Sugimoto M, Gromley A, Sherr CJ.; ''Hzf, a p53-responsive gene, regulates maintenance of the G2 phase checkpoint induced by DNA damage.''; PubMed Europe PMC Scholia
  68. Zhang J, Krishnamurthy PK, Johnson GV.; ''Cdk5 phosphorylates p53 and regulates its activity.''; PubMed Europe PMC Scholia
  69. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ.; ''The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.''; PubMed Europe PMC Scholia
  70. Luciani MG, Hutchins JR, Zheleva D, Hupp TR.; ''The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A.''; PubMed Europe PMC Scholia
  71. Murray-Zmijewski F, Slee EA, Lu X.; ''A complex barcode underlies the heterogeneous response of p53 to stress.''; PubMed Europe PMC Scholia
  72. Budhram-Mahadeo VS, Bowen S, Lee S, Perez-Sanchez C, Ensor E, Morris PJ, Latchman DS.; ''Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression.''; PubMed Europe PMC Scholia
  73. An W, Kim J, Roeder RG.; ''Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53.''; PubMed Europe PMC Scholia
  74. Tanaka T, Ohkubo S, Tatsuno I, Prives C.; ''hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes.''; PubMed Europe PMC Scholia
  75. Budram-Mahadeo V, Morris PJ, Latchman DS.; ''The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1).''; PubMed Europe PMC Scholia
  76. Wilson AM, Morquette B, Abdouh M, Unsain N, Barker PA, Feinstein E, Bernier G, Di Polo A.; ''ASPP1/2 regulate p53-dependent death of retinal ganglion cells through PUMA and Fas/CD95 activation in vivo.''; PubMed Europe PMC Scholia
  77. Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB.; ''AMID is a p53-inducible gene downregulated in tumors.''; PubMed Europe PMC Scholia
  78. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y.; ''Enhanced phosphorylation of p53 by ATM in response to DNA damage.''; PubMed Europe PMC Scholia
  79. Budhram-Mahadeo V, Morris PJ, Smith MD, Midgley CA, Boxer LM, Latchman DS.; ''p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor.''; PubMed Europe PMC Scholia
  80. Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, Khalil AM, Zuk O, Amit I, Rabani M, Attardi LD, Regev A, Lander ES, Jacks T, Rinn JL.; ''A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response.''; PubMed Europe PMC Scholia
  81. 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.; ''The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase.''; PubMed Europe PMC Scholia
  82. 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.; ''BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma.''; PubMed Europe PMC Scholia
  83. Jalota A, Singh K, Pavithra L, Kaul-Ghanekar R, Jameel S, Chattopadhyay S.; ''Tumor suppressor SMAR1 activates and stabilizes p53 through its arginine-serine-rich motif.''; PubMed Europe PMC Scholia
  84. Chehab NH, Malikzay A, Stavridi ES, Halazonetis TD.; ''Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage.''; PubMed Europe PMC Scholia
  85. Li Y, Park J, Piao L, Kong G, Kim Y, Park KA, Zhang T, Hong J, Hur GM, Seok JH, Choi SW, Yoo BC, Hemmings BA, Brazil DP, Kim SH, Park J.; ''PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage.''; PubMed Europe PMC Scholia
  86. Wu L, Ma CA, Zhao Y, Jain A.; ''Aurora B interacts with NIR-p53, leading to p53 phosphorylation in its DNA-binding domain and subsequent functional suppression.''; PubMed Europe PMC Scholia
  87. Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B.; ''14-3-3sigma is a p53-regulated inhibitor of G2/M progression.''; PubMed Europe PMC Scholia
  88. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B.; ''WAF1, a potential mediator of p53 tumor suppression.''; PubMed Europe PMC Scholia
  89. Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller SP, Lavin MF.; ''ATM associates with and phosphorylates p53: mapping the region of interaction.''; PubMed Europe PMC Scholia
  90. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD.; ''Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.''; PubMed Europe PMC Scholia
  91. Gupta S, Radha V, Furukawa Y, Swarup G.; ''Direct transcriptional activation of human caspase-1 by tumor suppressor p53.''; PubMed Europe PMC Scholia
  92. Park S, Kim D, Dan HC, Chen H, Testa JR, Cheng JQ.; ''Identification of Akt interaction protein PHF20/TZP that transcriptionally regulates p53.''; PubMed Europe PMC Scholia
  93. Shao S, Wang Y, Jin S, Song Y, Wang X, Fan W, Zhao Z, Fu M, Tong T, Dong L, Fan F, Xu N, Zhan Q.; ''Gadd45a interacts with aurora-A and inhibits its kinase activity.''; PubMed Europe PMC Scholia
  94. Saigusa K, Imoto I, Tanikawa C, Aoyagi M, Ohno K, Nakamura Y, Inazawa J.; ''RGC32, a novel p53-inducible gene, is located on centrosomes during mitosis and results in G2/M arrest.''; PubMed Europe PMC Scholia
  95. Das S, Raj L, Zhao B, Kimura Y, Bernstein A, Aaronson SA, Lee SW.; ''Hzf Determines cell survival upon genotoxic stress by modulating p53 transactivation.''; PubMed Europe PMC Scholia
  96. Takimoto R, El-Deiry WS.; ''Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site.''; PubMed Europe PMC Scholia
  97. Nakano K, Vousden KH.; ''PUMA, a novel proapoptotic gene, is induced by p53.''; PubMed Europe PMC Scholia
  98. Cui G, Park S, Badeaux AI, Kim D, Lee J, Thompson JR, Yan F, Kaneko S, Yuan Z, Botuyan MV, Bedford MT, Cheng JQ, Mer G.; ''PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53.''; PubMed Europe PMC Scholia
  99. Sánchez R, Pantoja-Uceda D, Prieto J, Diercks T, Marcaida MJ, Montoya G, Campos-Olivas R, Blanco FJ.; ''Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase.''; PubMed Europe PMC Scholia
  100. D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G, Piaggio G, Fanciulli M, Appella E, Soddu S.; ''Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis.''; PubMed Europe PMC Scholia
  101. St Clair S, Giono L, Varmeh-Ziaie S, Resnick-Silverman L, Liu WJ, Padi A, Dastidar J, DaCosta A, Mattia M, Manfredi JJ.; ''DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter.''; PubMed Europe PMC Scholia
  102. Budhram-Mahadeo V, Fujita R, Bitsi S, Sicard P, Heads R.; ''Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults.''; PubMed Europe PMC Scholia
  103. Kim HL, Kim SU, Seo YR.; ''A novel role for Gadd45α in base excision repair: modulation of APE1 activity by the direct interaction of Gadd45α with PCNA.''; PubMed Europe PMC Scholia
  104. Liu X, Yue P, Khuri FR, Sun SY.; ''Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity.''; PubMed Europe PMC Scholia
  105. Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson RS, Wang M, Liang P.; ''NDRG1 is necessary for p53-dependent apoptosis.''; PubMed Europe PMC Scholia
  106. Phan RT, Dalla-Favera R.; ''The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells.''; PubMed Europe PMC Scholia
  107. Miyashita T, Reed JC.; ''Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.''; PubMed Europe PMC Scholia
  108. Facchin S, Lopreiato R, Ruzzene M, Marin O, Sartori G, Götz C, Montenarh M, Carignani G, Pinna LA.; ''Functional homology between yeast piD261/Bud32 and human PRPK: both phosphorylate p53 and PRPK partially complements piD261/Bud32 deficiency.''; PubMed Europe PMC Scholia
  109. Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, Kley N.; ''Induction of the growth inhibitor IGF-binding protein 3 by p53.''; PubMed Europe PMC Scholia
  110. Espinosa JM.; ''Mechanisms of regulatory diversity within the p53 transcriptional network.''; PubMed Europe PMC Scholia
  111. Ihrie RA, Reczek E, Horner JS, Khachatrian L, Sage J, Jacks T, Attardi LD.; ''Perp is a mediator of p53-dependent apoptosis in diverse cell types.''; PubMed Europe PMC Scholia
  112. Syed N, Smith P, Sullivan A, Spender LC, Dyer M, Karran L, O'Nions J, Allday M, Hoffmann I, Crawford D, Griffin B, Farrell PJ, Crook T.; ''Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies.''; PubMed Europe PMC Scholia
  113. Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS.; ''BID regulation by p53 contributes to chemosensitivity.''; PubMed Europe PMC Scholia
  114. Schilling T, Schleithoff ES, Kairat A, Melino G, Stremmel W, Oren M, Krammer PH, Müller M.; ''Active transcription of the human FAS/CD95/TNFRSF6 gene involves the p53 family.''; PubMed Europe PMC Scholia
  115. Celardo I, Grespi F, Antonov A, Bernassola F, Garabadgiu AV, Melino G, Amelio I.; ''Caspase-1 is a novel target of p63 in tumor suppression.''; PubMed Europe PMC Scholia
  116. Rikhof B, Corn PG, El-Deiry WS.; ''Caspase 10 levels are increased following DNA damage in a p53-dependent manner.''; PubMed Europe PMC Scholia
  117. Ezzeddine N, Chen CY, Shyu AB.; ''Evidence providing new insights into TOB-promoted deadenylation and supporting a link between TOB's deadenylation-enhancing and antiproliferative activities.''; PubMed Europe PMC Scholia
  118. Jain N, Gupta S, Sudhakar Ch, Radha V, Swarup G.; ''Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin.''; PubMed Europe PMC Scholia
  119. Chan TA, Hermeking H, Lengauer C, Kinzler KW, Vogelstein B.; ''14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage.''; PubMed Europe PMC Scholia
  120. Hudson CD, Morris PJ, Latchman DS, Budhram-Mahadeo VS.; ''Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate.''; PubMed Europe PMC Scholia
  121. Li HH, Li AG, Sheppard HM, Liu X.; ''Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression.''; PubMed Europe PMC Scholia
  122. Fei P, Wang W, Kim SH, Wang S, Burns TF, Sax JK, Buzzai M, Dicker DT, McKenna WG, Bernhard EJ, El-Deiry WS.; ''Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth.''; PubMed Europe PMC Scholia
  123. Doidge R, Mittal S, Aslam A, Winkler GS.; ''The anti-proliferative activity of BTG/TOB proteins is mediated via the Caf1a (CNOT7) and Caf1b (CNOT8) deadenylase subunits of the Ccr4-not complex.''; PubMed Europe PMC Scholia
  124. Robinson RA, Lu X, Jones EY, Siebold C.; ''Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63, and p73.''; PubMed Europe PMC Scholia
  125. Varrault A, Ciani E, Apiou F, Bilanges B, Bilanges B, Hoffmann A, Pantaloni C, Bockaert J, Spengler D, Journot L.; ''hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer.''; PubMed Europe PMC Scholia
  126. Giam M, Okamoto T, Mintern JD, Strasser A, Bouillet P.; ''Bcl-2 family member Bcl-G is not a proapoptotic protein.''; PubMed Europe PMC Scholia
  127. Robles AI, Bemmels NA, Foraker AB, Harris CC.; ''APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis.''; PubMed Europe PMC Scholia
  128. Horiuchi M, Takeuchi K, Noda N, Muroya N, Suzuki T, Nakamura T, Kawamura-Tsuzuku J, Takahasi K, Yamamoto T, Inagaki F.; ''Structural basis for the antiproliferative activity of the Tob-hCaf1 complex.''; PubMed Europe PMC Scholia
  129. Wilson AM, Chiodo VA, Boye SL, Brecha NC, Hauswirth WW, Di Polo A.; ''Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is required for neuronal survival after axonal injury.''; PubMed Europe PMC Scholia
  130. Chang J, Cizmecioglu O, Hoffmann I, Rhee K.; ''PLK2 phosphorylation is critical for CPAP function in procentriole formation during the centrosome cycle.''; PubMed Europe PMC Scholia
  131. 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.; ''KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene.''; PubMed Europe PMC Scholia
  132. Li CQ, Robles AI, Hanigan CL, Hofseth LJ, Trudel LJ, Harris CC, Wogan GN.; ''Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53.''; PubMed Europe PMC Scholia
  133. Aksoy O, Chicas A, Zeng T, Zhao Z, McCurrach M, Wang X, Lowe SW.; ''The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence.''; PubMed Europe PMC Scholia
  134. 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.; ''BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma.''; PubMed Europe PMC Scholia
  135. Barsotti AM, Prives C.; ''Noncoding RNAs: the missing "linc" in p53-mediated repression.''; PubMed Europe PMC Scholia
  136. Guan B, Yue P, Clayman GL, Sun SY.; ''Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene.''; PubMed Europe PMC Scholia
  137. Liu X, Yue P, Khuri FR, Sun SY.; ''p53 upregulates death receptor 4 expression through an intronic p53 binding site.''; PubMed Europe PMC Scholia
  138. Benson EK, Mungamuri SK, Attie O, Kracikova M, Sachidanandam R, Manfredi JJ, Aaronson SA.; ''p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes.''; PubMed Europe PMC Scholia
  139. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB.; ''AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.''; PubMed Europe PMC Scholia
  140. Davies L, Gray D, Spiller D, White MR, Damato B, Grierson I, Paraoan L.; ''P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
116687view14:18, 9 May 2021EweitzModified title
114818view16:31, 25 January 2021ReactomeTeamReactome version 75
113263view11:33, 2 November 2020ReactomeTeamReactome version 74
112478view15:43, 9 October 2020ReactomeTeamReactome version 73
101389view11:27, 1 November 2018ReactomeTeamreactome version 66
100927view21:03, 31 October 2018ReactomeTeamreactome version 65
100466view19:37, 31 October 2018ReactomeTeamreactome version 64
100012view16:21, 31 October 2018ReactomeTeamreactome version 63
99565view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99189view12:42, 31 October 2018ReactomeTeamreactome version 62
93781view13:36, 16 August 2017ReactomeTeamreactome version 61
93313view11:20, 9 August 2017ReactomeTeamreactome version 61
87634view08:54, 25 July 2016LindarieswijkOntology Term : 'p53 signaling pathway' added !
86399view09:17, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)ComplexR-HSA-6799788 (Reactome)
(p-S15,S20-TP53,TP63,TP73):PPP1R13LComplexR-HSA-6799745 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active AKTComplexR-HSA-202072 (Reactome)
BANP ProteinQ8N9N5 (Uniprot-TrEMBL)
BANPProteinQ8N9N5 (Uniprot-TrEMBL)
Me2-K370,K382-TP53 TetramerComplexR-HSA-3222245 (Reactome)
Me2K-370,382-TP53 ProteinP04637 (Uniprot-TrEMBL)
PHF20 ProteinQ9BVI0 (Uniprot-TrEMBL)
PHF20:Me2-K370,K382-TP53 TetramerComplexR-HSA-3222249 (Reactome)
PHF20ProteinQ9BVI0 (Uniprot-TrEMBL)
POU4F1 ProteinQ01851 (Uniprot-TrEMBL)
POU4F1ProteinQ01851 (Uniprot-TrEMBL)
POU4F2 ProteinQ12837 (Uniprot-TrEMBL)
POU4F2ProteinQ12837 (Uniprot-TrEMBL)
PPP1R13B ProteinQ96KQ4 (Uniprot-TrEMBL)
PPP1R13B,TP53BP2ComplexR-HSA-6799786 (Reactome)
PPP1R13L ProteinQ8WUF5 (Uniprot-TrEMBL)
PPP1R13LProteinQ8WUF5 (Uniprot-TrEMBL)
Regulation of TP53

Activity through

Phosphorylation		PathwayR-HSA-6804756 (Reactome) 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.

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).

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).

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).

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).

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).

TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 Regulates

Transcription of

Cell Cycle Genes		PathwayR-HSA-6791312 (Reactome) Under a variety of stress conditions, TP53 (p53), stabilized by stress-induced phosphorylation at least on S15 and S20 serine residues, can induce the transcription of genes involved in cell cycle arrest. Cell cycle arrest provides cells an opportunity to repair the damage before division, thus preventing the transmission of genetic errors to daughter cells. In addition, it allows cells to attempt a recovery from the damage and survive, preventing premature cell death.

TP53 controls transcription of genes involved in both G1 and G2 cell cycle arrest. The most prominent TP53 target involved in G1 arrest is the inhibitor of cyclin-dependent kinases CDKN1A (p21). CDKN1A is one of the earliest genes induced by TP53 (El-Deiry et al. 1993). CDKN1A binds and inactivates CDK2 in complex with cyclin A (CCNA) or E (CCNE), thus preventing G1/S transition (Harper et al. 1993). Nevertheless, under prolonged stress, the cell destiny may be diverted towards an apoptotic outcome. For instance, in case of an irreversible damage, TP53 can induce transcription of an RNA binding protein PCBP4, which can bind and destabilize CDKN1A mRNA, thus alleviating G1 arrest and directing the affected cell towards G2 arrest and, possibly, apoptosis (Zhu and Chen 2000, Scoumanne et al. 2011). Expression of E2F7 is directly induced by TP53. E2F7 contributes to G1 cell cycle arrest by repressing transcription of E2F1, a transcription factor that promotes expression of many genes needed for G1/S transition (Aksoy et al. 2012, Carvajal et al. 2012). ARID3A is a direct transcriptional target of TP53 (Ma et al. 2003) that may promote G1 arrest by cooperating with TP53 in induction of CDKN1A transcription (Lestari et al. 2012). However, ARID3A may also promote G1/S transition by stimulating transcriptional activity of E2F1 (Suzuki et al. 1998, Peeper et al. 2002).

TP53 contributes to the establishment of G2 arrest by inducing transcription of GADD45A and SFN, and by inhibiting transcription of CDC25C. TP53 induces GADD45A transcription in cooperation with chromatin modifying enzymes EP300, PRMT1 and CARM1 (An et al. 2004). GADD45A binds Aurora kinase A (AURKA), inhibiting its catalytic activity and preventing AURKA-mediated G2/M transition (Shao et al. 2006, Sanchez et al. 2010). GADD45A also forms a complex with PCNA. PCNA is involved in both normal and repair DNA synthesis. The effect of GADD45 interaction with PCNA, if any, on S phase progression, G2 arrest and DNA repair is not known (Smith et al. 1994, Hall et al. 1995, Sanchez et al. 2010, Kim et al. 2013). SFN (14-3-3-sigma) is induced by TP53 (Hermeking et al. 1997) and contributes to G2 arrest by binding to the complex of CDK1 and CCNB1 (cyclin B1) and preventing its translocation to the nucleus. Phosphorylation of a number of nuclear proteins by the complex of CDK1 and CCNB1 is needed for G2/M transition (Chan et al. 1999). While promoting G2 arrest, SFN can simultaneously inhibit apoptosis by binding to BAX and preventing its translocation to mitochondria, a step involved in cytochrome C release (Samuel et al. 2001). TP53 binds the promoter of the CDC25C gene in cooperation with the transcriptional repressor E2F4 and represses CDC25C transcription, thus maintaining G2 arrest (St Clair et al. 2004, Benson et al. 2014).

Several direct transcriptional targets of TP53 are involved in cell cycle arrest but their mechanism of action is still unknown. BTG2 is induced by TP53, leading to cessation of cellular proliferation (Rouault et al. 1996, Duriez et al. 2002). BTG2 binds to the CCR4-NOT complex and promotes mRNA deadenylation activity of this complex. Interaction between BTG2 and CCR4-NOT is needed for the antiproliferative activity of BTG2, but the underlying mechanism has not been elucidated (Rouault et al. 1998, Mauxion et al. 2008, Horiuchi et al. 2009, Doidge et al. 2012, Ezzeddine et al. 2012). Two polo-like kinases, PLK2 and PLK3, are direct transcriptional targets of TP53. TP53-mediated induction of PLK2 may be important for prevention of mitotic catastrophe after spindle damage (Burns et al. 2003). PLK2 is involved in the regulation of centrosome duplication through phosphorylation of centrosome-related proteins CENPJ (Chang et al. 2010) and NPM1 (Krause and Hoffmann 2010). PLK2 is frequently transcriptionally silenced through promoter methylation in B-cell malignancies (Syed et al. 2006). Induction of PLK3 transcription by TP53 (Jen and Cheung 2005) may be important for coordination of M phase events through PLK3-mediated nuclear accumulation of CDC25C (Bahassi et al. 2004). RGCC is induced by TP53 and implicated in cell cycle regulation, possibly through its association with PLK1 (Saigusa et al. 2007). PLAGL1 (ZAC1) is a zinc finger protein directly transcriptionally induced by TP53 (Rozenfeld-Granot et al. 2002). PLAGL1 expression is frequently lost in cancer (Varrault et al. 1998) and PLAGL1 has been implicated in both cell cycle arrest and apoptosis (Spengler et al. 1997), but its mechanism of action remains unknown.

The zinc finger transcription factor ZNF385A (HZF) is a direct transcriptional target of TP53 that can form a complex with TP53 and facilitate TP53-mediated induction of CDKN1A and SFN (14-3-3 sigma) transcription (Das et al. 2007).

For a review of the role of TP53 in cell cycle arrest and cell cycle transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.

TP53 Regulates

Transcription of

Cell Death Genes		PathwayR-HSA-5633008 (Reactome) 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.

TP53 TetramerComplexR-HSA-3209194 (Reactome)
TP53:BANPComplexR-HSA-3221977 (Reactome)
TP53BP2 ProteinQ13625 (Uniprot-TrEMBL)
TP63 ProteinQ9H3D4 (Uniprot-TrEMBL)
TP73 ProteinO15350 (Uniprot-TrEMBL)
ZNF385A Gene ProteinENSG00000161642 (Ensembl)
ZNF385A GeneGeneProductENSG00000161642 (Ensembl)
ZNF385A ProteinQ96PM9 (Uniprot-TrEMBL)
ZNF385AProteinQ96PM9 (Uniprot-TrEMBL)
p-S15,S20-TP53 Tetramer:POU4F1ComplexR-HSA-6804394 (Reactome)
p-S15,S20-TP53 Tetramer:POU4F2ComplexR-HSA-6804423 (Reactome)
p-S15,S20-TP53

Tetramer:ZNF385A

Gene		ComplexR-HSA-6803418 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AComplexR-HSA-6803718 (Reactome)
p-S15,S20-TP53 TetramerComplexR-HSA-3222171 (Reactome)
p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15,S20-TP53,TP63,TP73ComplexR-HSA-6798076 (Reactome)
p-S291-PHF20ProteinQ9BVI0 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)ArrowR-HSA-6799777 (Reactome)
(p-S15,S20-TP53,TP63,TP73):PPP1R13LArrowR-HSA-6799761 (Reactome)
ADPArrowR-HSA-6805785 (Reactome)
ATPR-HSA-6805785 (Reactome)
Active AKTmim-catalysisR-HSA-6805785 (Reactome)
BANPR-HSA-3221982 (Reactome)
Me2-K370,K382-TP53 TetramerR-HSA-3222259 (Reactome)
PHF20:Me2-K370,K382-TP53 TetramerArrowR-HSA-3222259 (Reactome)
PHF20R-HSA-3222259 (Reactome)
PHF20R-HSA-6805785 (Reactome)
POU4F1R-HSA-6804402 (Reactome)
POU4F2R-HSA-6804425 (Reactome)
PPP1R13B,TP53BP2R-HSA-6799777 (Reactome)
PPP1R13LR-HSA-6799761 (Reactome)
R-HSA-3221982 (Reactome) BANP (SMAR1) binds TP53 (p53) and is implicated in both positive (Kaul et al. 2003, Jalota et al. 2005) and negative regulation of TP53 transcriptional activity (Pavithra et al. 2009, Sinha et al. 2010).
R-HSA-3222259 (Reactome) PHF20 binds TP53 (p53) dimethylated at lysine residues K370 and K382 by unidentified protein lysine methyltransferase(s). PHF20 binding interferes with MDM2 binding to TP53, thus resulting in TP53 stabilization (Cui et al. 2012).
R-HSA-6799761 (Reactome) PPP1R13L encodes the inhibitory member of the ASPP family - iASPP. PPP1R13L binds TP53 (p53) and inhibits its pro-apoptotic transcriptional activity. PPP1R13L cooperates with RAS, adenovirus protein E1A and the human papillomavirus protein E7 in cell transformation (Bergamaschi et al. 2003, Wilson et al. 2014). The C-terminus of PPP1R13L consists of four ankyrin repeats and an SH3 domain that form a p53-binding site. PPP1R13L binds the DNA binding site of TP53 (Robinson et al. 2008). PPP1R13L also interacts with p53 family members TP63 (p63) and TP73 (p73) (Robinson et al. 2008) and inhibits their pro-apoptotic transcriptional activity (Cai et al. 2012).
R-HSA-6799777 (Reactome) TP53 (p53) forms a complex with PPP1R13B (ASPP1) or TP53BP2 (ASPP2). This interaction involves the DNA binding domain of TP53 and the C-terminus of ASSP proteins (Samuels-Lev et al. 2001, Patel et al. 2008). ASPP proteins can also form a complex with p53 family members TP63 (p63) and TP73 (p73) (Robinson et al. 2008, Patel et al. 2008). ASPP proteins enhance the binding of p53 family members to promoters of pro-apoptotic genes and promote their transcription, but do not affect the transcription of cell cycle regulators. ASPP proteins are frequently down-regulated in breast cancers that express wild-type TP53 (Samuels-Lev et al. 2001, Bergamaschi et al. 2004).
R-HSA-6803425 (Reactome) TP53 (p53) binds to at least one of the three putative p53 response elements in the promoter of the human ZNF385A (HZF) gene (Das et al. 2007). In the mouse Znf385a gene, the p53 response element is in the first intron and also binds Tp53 (Sugimoto et al. 2006).
R-HSA-6803437 (Reactome) Binding of TP53 (p53) to the p53 response element(s) in the promoter of the ZNF385A (HZF) gene stimulates ZNF385A transcription (Das et al. 2007). TP53-mediated induction of ZNF385A is conserved in mouse (Sugimoto et al. 2006, Das et al. 2007).
R-HSA-6803719 (Reactome) ZNF385A (HZF) forms a complex with TP53 (p53), interacting with the DNA binding domain of TP53. The complex of TP53 and ZNF385A associates with p53 response elements of cell cycle arrest genes, such as CDKN1A (p21) and stimulates their transcription. Under prolonged stress, ZNF385A undergoes ubiquitination and proteasome-mediated degradation, which coincides with expression of TP53-regulated pro-apoptotic genes (Das et al. 2007).
R-HSA-6804402 (Reactome) TP53 (p53) forms a complex with a transcription factor POU4F1 (BRN3A). This interaction involves the POU domain of POU4F1. Binding of TP53 to POU4F1 modulates the transcriptional activity of both proteins, but the exact mechanism has not been elucidated. TP53 inhibits POU4F1-mediated induction of BCL2 transcription (Budhram-Mahadeo et al. 1999). POU4F1 inhibits TP53-mediated induction of BAX and NOXA, but enhances TP53-mediated induction of CDKN1A (p21) (Budhram-Mahadeo et al. 2002, Hudson et al. 2005).
R-HSA-6804425 (Reactome) POU4F2 (BRN3B), similarly to POU4F1 (BRN3A), forms a complex with TP53 (p53). The interaction involves the POU domain of POU4F2 and the DNA binding domain of TP53. In contrast to POU4F1, binding of POU4F2 to TP53 enhances TP53-mediated transcriptional induction of pro-apoptotic targets such as BAX (Budhram-Mahadeo et al. 2006), NOXA and PUMA (Budhram-Mahadeo et al. 2014). The pro-apoptotic action of the complex of POU4F2 and TP53 may control the fate of cardiomyocytes in injured heart (Budhram-Mahadeo et al. 2014).
R-HSA-6805785 (Reactome) AKT phosphorylates PHF20 on serine residue S291 (Park et al. 2012, Li et al. 2013), triggering PHF20 translocation to the cytosol (Park et al. 2012).
R-HSA-6805792 (Reactome) PHF20 phosphorylated at serine S291 by AKT (Park et al. 2012, Li et al. 2013) translocates to the cytosol (Park et al. 2012). AKT thus prevents PHF20-mediated stimulation of TP53 (p53) activity (Park et al. 2012, Li et al. 2013).
TP53 TetramerR-HSA-3221982 (Reactome)
TP53:BANPArrowR-HSA-3221982 (Reactome)
ZNF385A GeneR-HSA-6803425 (Reactome)
ZNF385A GeneR-HSA-6803437 (Reactome)
ZNF385AArrowR-HSA-6803437 (Reactome)
ZNF385AR-HSA-6803719 (Reactome)
p-S15,S20-TP53 Tetramer:POU4F1ArrowR-HSA-6804402 (Reactome)
p-S15,S20-TP53 Tetramer:POU4F2ArrowR-HSA-6804425 (Reactome)
p-S15,S20-TP53

Tetramer:ZNF385A

Gene		ArrowR-HSA-6803425 (Reactome)
p-S15,S20-TP53

Tetramer:ZNF385A

Gene		ArrowR-HSA-6803437 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AArrowR-HSA-6803719 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6803425 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6803719 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6804402 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6804425 (Reactome)
p-S15,S20-TP53,TP63,TP73R-HSA-6799761 (Reactome)
p-S15,S20-TP53,TP63,TP73R-HSA-6799777 (Reactome)
p-S291-PHF20ArrowR-HSA-6805785 (Reactome)
p-S291-PHF20ArrowR-HSA-6805792 (Reactome)
p-S291-PHF20R-HSA-6805792 (Reactome)

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