TP53 Regulates Transcription of Cell Cycle Genes (Homo sapiens)

From WikiPathways

Revision as of 13:37, 16 August 2017 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
1, 3, 6, 11-14, 18...59, 803, 12, 25, 36, 7113, 94, 118706, 107, 11666, 12069, 1195918, 77414111, 1071, 43, 52, 9310639104137, 11, 10718, 23, 44, 77, 891044620, 44, 8923, 44, 10374, 8623, 29, 44, 56, 77...1209858, 74, 866, 1071434, 99, 105, 11146, 5751145269, 1194867, 1055144, 8918, 77116nucleoplasmcytosolRegulation of TP53ActivityCNOT2 CCNA2 CCNB1 CNOT7 ARID3A Gene GADD45A CDKN1A mRNA PCBP4:CDKN1A mRNARBL1 CNOT11 CDK2 CCNE1 E2F1 genep-S15,S20-TP53 TFDP2 CCNE2 SFN Dimer:BAXATPGADD45A RQCD1 SFNE2F7:E2F8PRMT1TNKS1BP1 p-S15,S20-TP53Tetramer:PCBP4 GeneBAX SFN Dimer:CCNB1:CDK1PCBP4p-S15,S20-TP53Tetramer:ZNF385A:CDKN1A GeneCNOT8 E2F7 GeneMitotic G2-G2/MphasesCNOT3 p-S589,S595-CENPJSFN CNOT6L E2F8 PCBP4 GeneCCNA2 CNOT6 E2F7 PLK2TP53 RegulatesTranscription ofCell Death Genesp-S15,S20-TP53Tetramer:PLK2 GeneRBL1 CNOT1 CDKN1ABTG2 p-S15,S20-TP53 p-S15,S20-TP53Tetramer:E2F4:(TFDP1,TFDP2):(RBL1,RBL2):CDC25C GeneAURKA CCNB1:CDK1p-S15,S20-TP53TetramerCyclinA:Cdk2:p21/p27complexp-S15,S20-TP53 CCNE:CDK2BAXRBL2 E2F8E2F1CNOT10 CNOT3 CCNE2 CNOT6L SFN Gene PLAGL1 GeneCCNB1 E2F7,E2F8 dimersADPp-S15,S20-TP53 CDKN1A CARM1 Deadenylation-dependent mRNA decayp-S15,S20-TP53 E2F7p-S191-CDC25CCDK2 p-S15,S20-TP53 BTG2:CCR4-NOTEP300 BTG2CENPJp-S15,S20-TP53Tetramer:ZNF385APCNA homotrimerEP300p-S15,S20-TP53 ZNF385A RGCCATPCDKN1A mRNARQCD1 TNKS1BP1 CCNE1 CNOT4 CDKN1A,CDKN1Bp-S15,S20-TP53 GADD45A:AURKAARID3A GeneE2F4:(TFDP1,TFDP2):(RBL1,RBL2)PCBP4 Gene AURKACDC25C Gene CNOT8 Mitotic G1-G1/SphasesBTG2 GeneE2F7,E2F8dimers:E2F1 GeneCDK1 CDKN1B E2F7 homodimerE2F8 PCBP4 CNOT7 ARID3AADPCNOT4 p-S15,S20-TP53Tetramer:E2F7 GeneCARM1CDKN1A E2F8 homodimerGADD45A:PCNASFN p-S15,S20-TP53 CDK2 p-S15,S20-TP53Tetramer:ARID3AGeneCDC25CTFDP1 BTG2 Gene RBL2 SFN GeneTFDP2 E2F1 gene p-S15,S20-TP53 ZNF385A GADD45AE2F7 Gene E2F7 p-S15,S20-TP53 RGCC GeneCDKN1B TFDP1 PCNA E2F8 CDKN1A CCNA:CDK2CCNA1 PLAGL1CDKN1A gene GADD45A GeneCCNA1 CNOT11 CNOT2 PLAGL1 Gene PLK3 Gene CDK1 PLK3CDK2 p-S15,S20-TP53Tetramer:ZNF385A:SFN GeneCCR4-NOT ComplexIntrinsic Pathwayfor ApoptosisCDKN1B E2F4 p-S4-NPM1E2F8 E2F4 p-S15,S20-TP53 p-S15,S20-TP53Tetramer:PLK3 Genep-S15,S20-TP53Tetramer:PLAGL1GeneE2F7 PLK2 GeneSFN ZNF385A RGCC Gene p-S15,S20-TP53:EP300:PRMT1:CARM1:GADD45A GenePRMT1 p-S15,S20-TP53Tetramer:RGCC GeneCNOT1 PLK3 GenePCNA NPM1CDKN1A geneCyclinE:CDK2:CDKN1A,CDKN1BE2F7 p-S15,S20-TP53Tetramer:BTG2 Genep-S15,S20-TP53 CNOT6 p-S15,S20-TP53 CNOT10 PLK2 Gene CDC25C GeneGADD45A Gene SFN Dimer444, 73, 110, 117107132, 8, 14-16, 19...1041204618, 775123, 10310, 17, 24, 33, 45...70144167, 1051163921, 42, 9622, 785969, 1197734, 99, 1051075, 9, 83


Description

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).<p>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).<p>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.<p>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).<p>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. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 6791312
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. 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
  2. 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
  3. 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
  4. Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMed Europe PMC
  5. Li J, Ran C, Li E, Gordon F, Comstock G, Siddiqui H, Cleghorn W, Chen HZ, Kornacker K, Liu CG, Pandit SK, Khanizadeh M, Weinstein M, Leone G, de Bruin A.; ''Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development.''; PubMed Europe PMC
  6. Zalmas LP, Zhao X, Graham AL, Fisher R, Reilly C, Coutts AS, La Thangue NB.; ''DNA-damage response control of E2F7 and E2F8.''; PubMed Europe PMC
  7. 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
  8. Fritz DT, Bergman N, Kilpatrick WJ, Wilusz CJ, Wilusz J.; ''Messenger RNA decay in mammalian cells: the exonuclease perspective.''; PubMed Europe PMC
  9. 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
  10. Liu X, Yue P, Khuri FR, Sun SY.; ''Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity.''; PubMed Europe PMC
  11. 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
  12. Santiago A, Li D, Zhao LY, Godsey A, Liao D.; ''p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1.''; PubMed Europe PMC
  13. Bergamaschi D, Samuels Y, Jin B, Duraisingham S, Crook T, Lu X.; ''ASPP1 and ASPP2: common activators of p53 family members.''; PubMed Europe PMC
  14. 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
  15. Lin Y, Ma W, Benchimol S.; ''Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis.''; PubMed Europe PMC
  16. 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
  17. Liu X, Yue P, Khuri FR, Sun SY.; ''p53 upregulates death receptor 4 expression through an intronic p53 binding site.''; PubMed Europe PMC
  18. Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMed Europe PMC
  19. Houseley J, Tollervey D.; ''The many pathways of RNA degradation.''; PubMed Europe PMC
  20. Brough D, Rothwell NJ.; ''Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death.''; PubMed Europe PMC
  21. Wilusz CJ, Wormington M, Peltz SW.; ''The cap-to-tail guide to mRNA turnover.''; PubMed Europe PMC
  22. Serrano M, Hannon GJ, Beach D.; ''A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.''; PubMed Europe PMC
  23. 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
  24. Gupta S, Radha V, Furukawa Y, Swarup G.; ''Direct transcriptional activation of human caspase-1 by tumor suppressor p53.''; PubMed Europe PMC
  25. Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMed Europe PMC
  26. 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
  27. Wu M, Xu LG, Su T, Tian Y, Zhai Z, Shu HB.; ''AMID is a p53-inducible gene downregulated in tumors.''; PubMed Europe PMC
  28. 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
  29. Wang X.; ''The expanding role of mitochondria in apoptosis.''; PubMed Europe PMC
  30. Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS.; ''BID regulation by p53 contributes to chemosensitivity.''; PubMed Europe PMC
  31. An W, Kim J, Roeder RG.; ''Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53.''; PubMed Europe PMC
  32. 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
  33. 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
  34. Pandit SK, Westendorp B, Nantasanti S, van Liere E, Tooten PC, Cornelissen PW, Toussaint MJ, Lamers WH, de Bruin A.; ''E2F8 is essential for polyploidization in mammalian cells.''; PubMed Europe PMC
  35. 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
  36. Kruiswijk F, Labuschagne CF, Vousden KH.; ''p53 in survival, death and metabolic health: a lifeguard with a licence to kill.''; PubMed Europe PMC
  37. 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
  38. 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
  39. Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMed Europe PMC
  40. 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
  41. Bruinsma W, Raaijmakers JA, Medema RH.; ''Switching Polo-like kinase-1 on and off in time and space.''; PubMed Europe PMC
  42. 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
  43. Logan N, Delavaine L, Graham A, Reilly C, Wilson J, Brummelkamp TR, Hijmans EM, Bernards R, La Thangue NB.; ''E2F-7: a distinctive E2F family member with an unusual organization of DNA-binding domains.''; PubMed Europe PMC
  44. Maiti B, Li J, de Bruin A, Gordon F, Timmers C, Opavsky R, Patil K, Tuttle J, Cleghorn W, Leone G.; ''Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation.''; PubMed Europe PMC
  45. 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
  46. Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP, Dremier S.; ''A requirement for cyclin D3-cyclin-dependent kinase (cdk)-4 assembly in the cyclic adenosine monophosphate-dependent proliferation of thyrocytes.''; PubMed Europe PMC
  47. Mauxion F, Faux C, Séraphin B.; ''The BTG2 protein is a general activator of mRNA deadenylation.''; PubMed Europe PMC
  48. Espinosa JM, Verdun RE, Emerson BM.; ''p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage.''; PubMed Europe PMC
  49. 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
  50. Rikhof B, Corn PG, El-Deiry WS.; ''Caspase 10 levels are increased following DNA damage in a p53-dependent manner.''; PubMed Europe PMC
  51. Contente A, Dittmer A, Koch MC, Roth J, Dobbelstein M.; ''A polymorphic microsatellite that mediates induction of PIG3 by p53.''; PubMed Europe PMC
  52. 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
  53. MacLachlan TK, El-Deiry WS.; ''Apoptotic threshold is lowered by p53 transactivation of caspase-6.''; PubMed Europe PMC
  54. Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D.; ''The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase.''; PubMed Europe PMC
  55. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M.; ''Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.''; PubMed Europe PMC
  56. Wang G, Jiang Q, Zhang C.; ''The role of mitotic kinases in coupling the centrosome cycle with the assembly of the mitotic spindle.''; PubMed Europe PMC
  57. Hiebert SW.; ''Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression.''; PubMed Europe PMC
  58. Bieging KT, Mello SS, Attardi LD.; ''Unravelling mechanisms of p53-mediated tumour suppression.''; PubMed Europe PMC
  59. Riley T, Sontag E, Chen P, Levine A.; ''Transcriptional control of human p53-regulated genes.''; PubMed Europe PMC
  60. 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
  61. Krause A, Hoffmann I.; ''Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4 triggers centriole duplication.''; PubMed Europe PMC
  62. 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
  63. Dupressoir A, Morel AP, Barbot W, Loireau MP, Corbo L, Heidmann T.; ''Identification of four families of yCCR4- and Mg2+-dependent endonuclease-related proteins in higher eukaryotes, and characterization of orthologs of yCCR4 with a conserved leucine-rich repeat essential for hCAF1/hPOP2 binding.''; PubMed Europe PMC
  64. Parker R, Song H.; ''The enzymes and control of eukaryotic mRNA turnover.''; PubMed Europe PMC
  65. Murray-Zmijewski F, Slee EA, Lu X.; ''A complex barcode underlies the heterogeneous response of p53 to stress.''; PubMed Europe PMC
  66. Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K.; ''The retinoblastoma protein binds to a family of E2F transcription factors.''; PubMed Europe PMC
  67. Lau NC, Kolkman A, van Schaik FM, Mulder KW, Pijnappel WW, Heck AJ, Timmers HT.; ''Human Ccr4-Not complexes contain variable deadenylase subunits.''; PubMed Europe PMC
  68. 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
  69. 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
  70. 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
  71. 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
  72. 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
  73. 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
  74. Robles AI, Bemmels NA, Foraker AB, Harris CC.; ''APAF-1 is a transcriptional target of p53 in DNA damage-induced apoptosis.''; PubMed Europe PMC
  75. O'Farrell PH.; ''Triggering the all-or-nothing switch into mitosis.''; PubMed Europe PMC
  76. 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
  77. 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
  78. 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
  79. 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
  80. Moore MJ.; ''From birth to death: the complex lives of eukaryotic mRNAs.''; PubMed Europe PMC
  81. Verdoodt B, Benzinger A, Popowicz GM, Holak TA, Hermeking H.; ''Characterization of 14-3-3sigma dimerization determinants: requirement of homodimerization for inhibition of cell proliferation.''; PubMed Europe PMC
  82. 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
  83. 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
  84. 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
  85. Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMed Europe PMC
  86. 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
  87. 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
  88. Cobrinik D.; ''Pocket proteins and cell cycle control.''; PubMed Europe PMC
  89. Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML, Leone G.; ''The E2F1-3 transcription factors are essential for cellular proliferation.''; PubMed Europe PMC
  90. Wang W, Nacusi L, Sheaff RJ, Liu X.; ''Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection.''; PubMed Europe PMC
  91. 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
  92. Kruse JP, Gu W.; ''Modes of p53 regulation.''; PubMed Europe PMC
  93. Meek DW, Anderson CW.; ''Posttranslational modification of p53: cooperative integrators of function.''; PubMed Europe PMC
  94. 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
  95. 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
  96. 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
  97. Fosbrink M, Cudrici C, Niculescu F, Badea TC, David S, Shamsuddin A, Shin ML, Rus H.; ''Overexpression of RGC-32 in colon cancer and other tumors.''; PubMed Europe PMC
  98. Phan RT, Dalla-Favera R.; ''The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells.''; PubMed Europe PMC
  99. Chittenden T, Livingston DM, Kaelin WG.; ''The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein.''; PubMed Europe PMC
  100. Varrault A, Ciani E, Apiou F, 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
  101. 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
  102. 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
  103. 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
  104. 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
  105. Thurlings I, Martínez-López LM, Westendorp B, Zijp M, Kuiper R, Tooten P, Kent LN, Leone G, Vos HJ, Burgering B, de Bruin A.; ''Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer.''; PubMed Europe PMC
  106. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed Europe PMC
  107. Jen KY, Cheung VG.; ''Identification of novel p53 target genes in ionizing radiation response.''; PubMed Europe PMC
  108. Sadasivam S, DeCaprio JA.; ''The DREAM complex: master coordinator of cell cycle-dependent gene expression.''; PubMed Europe PMC
  109. Di Stefano L, Jensen MR, Helin K.; ''E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes.''; PubMed Europe PMC
  110. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC
  111. 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
  112. Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS.; ''Characterisation of the interaction between PCNA and Gadd45.''; PubMed Europe PMC
  113. Parry D, Bates S, Mann DJ, Peters G.; ''Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.''; PubMed Europe PMC
  114. Miyashita T, Reed JC.; ''Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.''; PubMed Europe PMC
  115. 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
  116. 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
  117. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMed Europe PMC
  118. 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
  119. 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
  120. 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
  121. Nakano K, Vousden KH.; ''PUMA, a novel proapoptotic gene, is induced by p53.''; PubMed Europe PMC
  122. Guo B, Godzik A, Reed JC.; ''Bcl-G, a novel pro-apoptotic member of the Bcl-2 family.''; PubMed Europe PMC
  123. Park WR, Nakamura Y.; ''p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway.''; PubMed Europe PMC
  124. 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
  125. 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
  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
  127. 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
  128. Bahassi el M, Hennigan RF, Myer DL, Stambrook PJ.; ''Cdc25C phosphorylation on serine 191 by Plk3 promotes its nuclear translocation.''; PubMed Europe PMC
  129. Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y.; ''Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.''; PubMed Europe PMC
  130. 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
  131. Takimoto R, El-Deiry WS.; ''Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site.''; PubMed Europe PMC
  132. 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
  133. 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
  134. 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
  135. Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMed Europe PMC
  136. Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMed Europe PMC
  137. Mantovani F, Zannini A, Rustighi A, Del Sal G.; ''Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships.''; PubMed Europe PMC
  138. Garneau NL, Wilusz J, Wilusz CJ.; ''The highways and byways of mRNA decay.''; PubMed Europe PMC
  139. 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

History

View all...
CompareRevisionActionTimeUserComment
101304view11:19, 1 November 2018ReactomeTeamreactome version 66
100841view20:50, 31 October 2018ReactomeTeamreactome version 65
100382view19:25, 31 October 2018ReactomeTeamreactome version 64
99929view16:08, 31 October 2018ReactomeTeamreactome version 63
99484view14:41, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99137view12:40, 31 October 2018ReactomeTeamreactome version 62
93809view13:37, 16 August 2017ReactomeTeamreactome version 61
93351view11:21, 9 August 2017ReactomeTeamreactome version 61
88397view15:19, 4 August 2016FehrhartOntology Term : 'regulatory pathway' added !
88396view15:19, 4 August 2016FehrhartOntology Term : 'cell cycle pathway' added !
86435view09:18, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ARID3A Gene ProteinENSG00000116017 (Ensembl)
ARID3A GeneGeneProductENSG00000116017 (Ensembl)
ARID3AProteinQ99856 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
AURKA ProteinO14965 (Uniprot-TrEMBL)
AURKAProteinO14965 (Uniprot-TrEMBL)
BAX ProteinQ07812 (Uniprot-TrEMBL)
BAXProteinQ07812 (Uniprot-TrEMBL)
BTG2 Gene ProteinENSG00000159388 (Ensembl)
BTG2 GeneGeneProductENSG00000159388 (Ensembl)
BTG2 ProteinP78543 (Uniprot-TrEMBL)
BTG2:CCR4-NOTComplexR-HSA-6798046 (Reactome)
BTG2ProteinP78543 (Uniprot-TrEMBL)
CARM1 ProteinQ86X55 (Uniprot-TrEMBL)
CARM1ProteinQ86X55 (Uniprot-TrEMBL)
CCNA1 ProteinP78396 (Uniprot-TrEMBL)
CCNA2 ProteinP20248 (Uniprot-TrEMBL)
CCNA:CDK2ComplexR-HSA-141608 (Reactome)
CCNB1 ProteinP14635 (Uniprot-TrEMBL)
CCNB1:CDK1ComplexR-HSA-6803876 (Reactome)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CCNE2 ProteinO96020 (Uniprot-TrEMBL)
CCNE:CDK2ComplexR-HSA-68374 (Reactome)
CCR4-NOT ComplexComplexR-HSA-429896 (Reactome) The human CCR4-NOT complex contains 7 core subunits: CNOT1, CNOT2, CNOT3, CNOT9/RCD1, CNOT10, TAB182, and C2ORF29. Complexes contain either CNOT7 or CNOT8 (with CNOT8-containing complexes apparently involved in nuclear RNA splicing and CNOT7-containing complexes involved in cytoplasmic mRNA decay) and CNOT6 or CNOT6L. CNOT6 and CNOT6L are catalytic exoribonucleases. CNOT7 and CNOT8 also have ribonuclease activity. CNOT1 is the largest subunit and, based on yeast two-hybrid assays, interacts with CNOT2, CNOT7, CNOT8, and CNOT9, thus acting as a scaffold.
CDC25C Gene ProteinENSG00000158402 (Ensembl)
CDC25C GeneGeneProductENSG00000158402 (Ensembl)
CDC25CProteinP30307 (Uniprot-TrEMBL)
CDK1 ProteinP06493 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1A gene ProteinENSG00000124762 (Ensembl)
CDKN1A geneGeneProductENSG00000124762 (Ensembl)
CDKN1A mRNA ProteinENST00000244741 (Ensembl)
CDKN1A mRNARnaENST00000244741 (Ensembl)
CDKN1A,CDKN1BComplexR-HSA-182558 (Reactome)
CDKN1AProteinP38936 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CENPJProteinQ9HC77 (Uniprot-TrEMBL)
CNOT1 ProteinA5YKK6 (Uniprot-TrEMBL)
CNOT10 ProteinQ9H9A5 (Uniprot-TrEMBL)
CNOT11 ProteinQ9UKZ1 (Uniprot-TrEMBL)
CNOT2 ProteinQ9NZN8 (Uniprot-TrEMBL)
CNOT3 ProteinO75175 (Uniprot-TrEMBL)
CNOT4 ProteinO95628 (Uniprot-TrEMBL)
CNOT6 ProteinQ9ULM6 (Uniprot-TrEMBL)
CNOT6L ProteinQ96LI5 (Uniprot-TrEMBL)
CNOT7 ProteinQ9UIV1 (Uniprot-TrEMBL)
CNOT8 ProteinQ9UFF9 (Uniprot-TrEMBL)
Cyclin

A:Cdk2:p21/p27

complex
ComplexR-HSA-187926 (Reactome)
Cyclin E:CDK2:CDKN1A,CDKN1BComplexR-HSA-68376 (Reactome)
Deadenylation-dependent