TP53 Regulates Transcription of Cell Cycle Genes (Homo sapiens)

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1-3, 11, 16...1071775, 6, 34, 68, 105...55, 90, 1343, 69, 10010711, 865, 43, 10949, 62, 865, 65, 6, 4455, 1343371118, 1272, 6070, 71120318168, 125316337638, 47, 78, 101, 11977621286197, 12016, 42, 79, 130102312, 6032, 91, 112, 11895, 1025, 6, 68, 109, 12568, 12511, 48, 8649, 86cytosolnucleoplasmSFN Dimerp-S15,S20-TP53Tetramer:RGCC GeneE2F4:(TFDP1,TFDP2):(RBL1,RBL2)Mitotic G2-G2/Mphasesp-S15,S20-TP53Tetramer:PLK3 GeneCCNB1 Regulation of TP53ActivityPCNA homotrimerCNOT8 CCNA2 p-S15,S20-TP53 p-S15,S20-TP53 CNOT2 TP53 RegulatesTranscription ofCell Death Genesp-S15,S20-TP53 E2F1 genep-S589,S595-CENPJE2F7,E2F8dimers:E2F1 GeneEP300 p-S4-NPM1CCNE1 ZNF385A AURKACDKN1B p-S15,S20-TP53 E2F4 GADD45A:PCNACCNE2 SFN Dimer:CCNB1:CDK1CDK2 SFN GeneBTG2 SFN CARM1 CNOT11 CDKN1A,CDKN1BTFDP2 E2F1 gene SFN Dimer:BAXCDC25C Gene PLK3 Gene CDKN1A mRNACNOT1 CNOT10 PCBP4CCNA1 ZNF385A ARID3Ap-S15,S20-TP53Tetramer:ZNF385A:CDKN1A GeneCNOT7 p-S15,S20-TP53 ARID3A GeneMitotic G1-G1/SphasesSFNp-S15,S20-TP53Tetramer:BTG2 GenePLK2 Gene p-S15,S20-TP53Tetramer:ZNF385ACDK1 BAX PRMT1p-S15,S20-TP53 TFDP1 CCR4-NOT ComplexCDKN1ACCNE:CDK2GADD45AE2F8 homodimerCNOT6 p-S191-CDC25CE2F8 CNOT4 NPM1ADPCDKN1A geneE2F1BTG2 GenePCNA CDKN1A mRNA p-S15,S20-TP53 p-S15,S20-TP53Tetramer:PCBP4 GeneBAXRGCC Gene PLAGL1 GeneCDKN1A CNOT3 E2F7 homodimerRQCD1 PLK3 GeneCCNB1:CDK1p-S15,S20-TP53Tetramer:E2F7 GeneE2F8RGCC GeneE2F7,E2F8 dimersGADD45A GenePLAGL1TNKS1BP1 p-S15,S20-TP53Tetramer:E2F4:(TFDP1,TFDP2):(RBL1,RBL2):CDC25C GeneRBL1 CNOT3 GADD45A CDKN1A gene ARID3A Gene CyclinE:CDK2:CDKN1A,CDKN1BCNOT10 p-S15,S20-TP53 CDKN1B PCBP4 GeneE2F8 p-S15,S20-TP53 PLAGL1 Gene E2F8 CDC25C GeneCDK2 CNOT11 E2F7 p-S15,S20-TP53 p-S15,S20-TP53 SFN CNOT1 CNOT2 CCNE2 CNOT6L PLK2p-S15,S20-TP53Tetramer:PLK2 GeneCyclinA:Cdk2:p21/p27complexTFDP2 CNOT6L p-S15,S20-TP53Tetramer:ZNF385A:SFN Genep-S15,S20-TP53 CDK2 TFDP1 CCNA:CDK2SFN GADD45A:AURKAPLK3RBL2 ATPPRMT1 PCBP4 Gene BTG2:CCR4-NOTPCNA E2F7 CNOT8 CCNA2 CDKN1A CCNB1 CDKN1A CCNA1 PLK2 GeneSFN Gene CARM1E2F7 Genep-S15,S20-TP53 E2F7 EP300RBL1 CDK2 CCNE1 E2F7GADD45A Gene CNOT4 ADPE2F7 Gene PCBP4 E2F8 AURKA Intrinsic Pathwayfor Apoptosisp-S15,S20-TP53:EP300:PRMT1:CARM1:GADD45A GeneE2F4 p-S15,S20-TP53 PCBP4:CDKN1A mRNAE2F7 CDK1 CDKN1B Deadenylation-dependent mRNA decayZNF385A RQCD1 RBL2 CENPJATPCNOT7 BTG2 Gene CNOT6 p-S15,S20-TP53TetramerGADD45A p-S15,S20-TP53Tetramer:ARID3AGeneRGCCCDC25CTNKS1BP1 E2F7:E2F8BTG2p-S15,S20-TP53Tetramer:PLAGL1Gene314, 18, 22, 25, 39...2, 6032, 112, 1187129, 110, 11710262168, 12541, 56, 75868112, 92, 93, 13763, 67118, 1273586120687, 9, 10, 13-15, 17...8, 19, 21, 64, 80...7743, 10933107


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>

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

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  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
  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
  98. Phan RT, Dalla-Favera R.; ''The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells.''; PubMed
  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
  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
  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
  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
  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
  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
  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
  106. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed
  107. Jen KY, Cheung VG.; ''Identification of novel p53 target genes in ionizing radiation response.''; PubMed
  108. Sadasivam S, DeCaprio JA.; ''The DREAM complex: master coordinator of cell cycle-dependent gene expression.''; PubMed
  109. Di Stefano L, Jensen MR, Helin K.; ''E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes.''; PubMed
  110. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed
  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
  112. Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS.; ''Characterisation of the interaction between PCNA and Gadd45.''; PubMed
  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
  114. Miyashita T, Reed JC.; ''Tumor suppressor p53 is a direct transcriptional activator of the human bax gene.''; PubMed
  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
  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
  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
  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
  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
  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
  121. Nakano K, Vousden KH.; ''PUMA, a novel proapoptotic gene, is induced by p53.''; PubMed
  122. Guo B, Godzik A, Reed JC.; ''Bcl-G, a novel pro-apoptotic member of the Bcl-2 family.''; PubMed
  123. Park WR, Nakamura Y.; ''p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway.''; PubMed
  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
  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
  126. Giam M, Okamoto T, Mintern JD, Strasser A, Bouillet P.; ''Bcl-2 family member Bcl-G is not a proapoptotic protein.''; PubMed
  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
  128. Bahassi el M, Hennigan RF, Myer DL, Stambrook PJ.; ''Cdc25C phosphorylation on serine 191 by Plk3 promotes its nuclear translocation.''; PubMed
  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
  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
  131. Takimoto R, El-Deiry WS.; ''Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site.''; PubMed
  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
  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
  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
  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
  136. Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMed
  137. Mantovani F, Zannini A, Rustighi A, Del Sal G.; ''Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships.''; PubMed
  138. Garneau NL, Wilusz J, Wilusz CJ.; ''The highways and byways of mRNA decay.''; PubMed
  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

History

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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 mRNA decayPathwayR-HSA-429914 (Reactome) After undergoing rounds of translation, mRNA is normally destroyed by the deadenylation-dependent pathway. Though the trigger is unclear, deadenylation likely proceeds in two steps: one catalyzed by the PAN2-PAN3 complex that shortens the poly(A) tail from about 200 adenosine residues to about 80 residues and one catalyzed by the CCR4-NOT complex or by the PARN enzyme that shortens the tail to about 10-15 residues.
After deadenylation the mRNA is then hydrolyzed by either the 5' to 3' pathway or the 3' to 5' pathway. It is unknown what determinants target a mRNA to one pathway or the other.
The 5' to 3' pathway is initiated by binding of the Lsm1-7 complex to the 3' oligoadenylate tail followed by decapping by the DCP1-DCP2 complex. The 5' to 3' exoribonuclease XRN1 then hydrolyzes the remaining RNA.
The 3' to 5' pathway is initiated by the exosome complex at the 3' end of the mRNA. The exosome processively hydrolyzes the mRNA from 3' to 5', leaving only a capped oligoribonucleotide. The cap is then removed by the scavenging decapping enzyme DCPS.
E2F1 gene ProteinENSG00000101412 (Ensembl)
E2F1 geneGeneProductENSG00000101412 (Ensembl)
E2F1ProteinQ01094 (Uniprot-TrEMBL)
E2F4 ProteinQ16254 (Uniprot-TrEMBL)
E2F4:(TFDP1,TFDP2):(RBL1,RBL2)ComplexR-HSA-6798265 (Reactome)
E2F7 Gene ProteinENSG00000165891 (Ensembl)
E2F7 GeneGeneProductENSG00000165891 (Ensembl)
E2F7 ProteinQ96AV8 (Uniprot-TrEMBL)
E2F7 homodimerComplexR-HSA-8953000 (Reactome)
E2F7,E2F8 dimers:E2F1 GeneComplexR-HSA-6798354 (Reactome)
E2F7,E2F8 dimersComplexR-HSA-8953034 (Reactome)
E2F7:E2F8ComplexR-HSA-8953017 (Reactome)
E2F7ProteinQ96AV8 (Uniprot-TrEMBL)
E2F8 ProteinA0AVK6 (Uniprot-TrEMBL)
E2F8 homodimerComplexR-HSA-8953035 (Reactome)
E2F8ProteinA0AVK6 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
GADD45A Gene ProteinENSG00000116717 (Ensembl)
GADD45A GeneGeneProductENSG00000116717 (Ensembl)
GADD45A ProteinP24522 (Uniprot-TrEMBL)
GADD45A:AURKAComplexR-HSA-6791236 (Reactome)
GADD45A:PCNAComplexR-HSA-6791115 (Reactome)
GADD45AProteinP24522 (Uniprot-TrEMBL)
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome) Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.

During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).

During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.

Mitotic G2-G2/M phasesPathwayR-HSA-453274 (Reactome) Mitotic G2 (gap 2) phase is the second growth phase during eukaryotic mitotic cell cycle. G2 encompasses the interval between the completion of DNA synthesis and the beginning of mitosis. During G2, the cytoplasmic content of the cell increases. At G2/M transition, duplicated centrosomes mature and separate and CDK1:cyclin B complexes become active, setting the stage for spindle assembly and chromosome condensation that occur in the prophase of mitosis (O'Farrell 2001, Bruinsma et al. 2012, Jiang et al. 2014).
NPM1ProteinP06748 (Uniprot-TrEMBL)
PCBP4 Gene ProteinENSG00000090097 (Ensembl)
PCBP4 GeneGeneProductENSG00000090097 (Ensembl)
PCBP4 ProteinP57723 (Uniprot-TrEMBL)
PCBP4:CDKN1A mRNAComplexR-HSA-6803405 (Reactome)
PCBP4ProteinP57723 (Uniprot-TrEMBL)
PCNA ProteinP12004 (Uniprot-TrEMBL)
PCNA homotrimerComplexR-HSA-68440 (Reactome)
PLAGL1 Gene ProteinENSG00000118495 (Ensembl)
PLAGL1 GeneGeneProductENSG00000118495 (Ensembl)
PLAGL1ProteinQ9UM63 (Uniprot-TrEMBL)
PLK2 Gene ProteinENSG00000145632 (Ensembl)
PLK2 GeneGeneProductENSG00000145632 (Ensembl)
PLK2ProteinQ9NYY3 (Uniprot-TrEMBL)
PLK3 Gene ProteinENSG00000173846 (Ensembl)
PLK3 GeneGeneProductENSG00000173846 (Ensembl)
PLK3ProteinQ9H4B4 (Uniprot-TrEMBL)
PRMT1 ProteinQ99873 (Uniprot-TrEMBL)
PRMT1ProteinQ99873 (Uniprot-TrEMBL)
RBL1 ProteinP28749 (Uniprot-TrEMBL)
RBL2 ProteinQ08999 (Uniprot-TrEMBL)
RGCC Gene ProteinENSG00000102760 (Ensembl)
RGCC GeneGeneProductENSG00000102760 (Ensembl)
RGCCProteinQ9H4X1 (Uniprot-TrEMBL)
RQCD1 ProteinQ92600 (Uniprot-TrEMBL)
Regulation of TP53 ActivityPathwayR-HSA-5633007 (Reactome) Protein stability and transcriptional activity of TP53 (p53) tumor suppressor are regulated by post-translational modifications that include ubiquitination, phosphorylation, acetylation, methylation, sumoylation and prolyl-isomerization (Kruse and Gu 2009, Meek and Anderson 2009, Santiago et al. 2013, Mantovani et al. 2015). In addition to post-translational modifications, the activity of TP53 is also regulated by binding of transcription co-factors.

In unstressed cells, TP53 protein levels are low due to MDM2-mediated ubiquitination of TP53, which triggers proteasome-mediated degradation. In response to stress, TP53 undergoes stabilizing phosphorylation, mainly at serine residues S15 and S20. Several different kinases can phosphorylate TP53 at these sites, but the main S15 kinases are considered to be ATM and ATR, while the main S20 kinases are considered to be CHEK2 and CHEK1. Additional phosphorylation of TP53 at serine residue S46 promotes transcription of pro-apoptotic, rather than cell cycle arrest genes.

Acetylation mainly has a positive impact on transcriptional activity of TP53, while methylation can both positively and negatively regulate TP53.

Some posttranslational modifications regulate interaction of TP53 with transcriptional co-factors, some of which are themselves transcriptional targets of TP53.

For review of the complex network of TP53 regulation, please refer to Kruse and Gu 2009, and Meek and Anderson 2009.

SFN Dimer:BAXComplexR-HSA-6803894 (Reactome)
SFN Dimer:CCNB1:CDK1ComplexR-HSA-6803878 (Reactome)
SFN DimerComplexR-HSA-6803886 (Reactome)
SFN Gene ProteinENSG00000175793 (Ensembl)
SFN GeneGeneProductENSG00000175793 (Ensembl)
SFN ProteinP31947 (Uniprot-TrEMBL)
SFNProteinP31947 (Uniprot-TrEMBL)
TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TNKS1BP1 ProteinQ9C0C2 (Uniprot-TrEMBL)
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.

ZNF385A ProteinQ96PM9 (Uniprot-TrEMBL)
p-S15,S20-TP53

Tetramer:ARID3A

Gene
ComplexR-HSA-6791369 (Reactome)
p-S15,S20-TP53 Tetramer:BTG2 GeneComplexR-HSA-6798042 (Reactome)
p-S15,S20-TP53 Tetramer:E2F4:(TFDP1,TFDP2):(RBL1,RBL2):CDC25C GeneComplexR-HSA-6798290 (Reactome)
p-S15,S20-TP53 Tetramer:E2F7 GeneComplexR-HSA-6798303 (Reactome)
p-S15,S20-TP53 Tetramer:PCBP4 GeneComplexR-HSA-6803394 (Reactome)
p-S15,S20-TP53

Tetramer:PLAGL1

Gene
ComplexR-HSA-6803938 (Reactome)
p-S15,S20-TP53 Tetramer:PLK2 GeneComplexR-HSA-6801640 (Reactome)
p-S15,S20-TP53 Tetramer:PLK3 GeneComplexR-HSA-6802166 (Reactome)
p-S15,S20-TP53 Tetramer:RGCC GeneComplexR-HSA-6803916 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385A:CDKN1A GeneComplexR-HSA-6803802 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385A:SFN GeneComplexR-HSA-6803857 (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:EP300:PRMT1:CARM1:GADD45A GeneComplexR-HSA-3215149 (Reactome)
p-S191-CDC25CProteinP30307 (Uniprot-TrEMBL)
p-S4-NPM1ProteinP06748 (Uniprot-TrEMBL)
p-S589,S595-CENPJProteinQ9HC77 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-6801666 (Reactome)
ADPArrowR-HSA-6801675 (Reactome)
ADPArrowR-HSA-6802973 (Reactome)
ARID3A GeneR-HSA-6791363 (Reactome)
ARID3A GeneR-HSA-6791387 (Reactome)
ARID3AArrowR-HSA-6791363 (Reactome)
ATPR-HSA-6801666 (Reactome)
ATPR-HSA-6801675 (Reactome)
ATPR-HSA-6802973 (Reactome)
AURKAR-HSA-6791235 (Reactome)
BAXR-HSA-6803892 (Reactome)
BTG2 GeneR-HSA-6798020 (Reactome)
BTG2 GeneR-HSA-6798031 (Reactome)
BTG2:CCR4-NOTArrowR-HSA-6798044 (Reactome)
BTG2ArrowR-HSA-6798031 (Reactome)
BTG2R-HSA-6798044 (Reactome)
CARM1R-HSA-3215152 (Reactome)
CCNA:CDK2R-HSA-187934 (Reactome)
CCNB1:CDK1R-HSA-6803875 (Reactome)
CCNE:CDK2R-HSA-69562 (Reactome)
CCR4-NOT ComplexR-HSA-6798044 (Reactome)
CDC25C GeneR-HSA-6798268 (Reactome)
CDC25C GeneR-HSA-6798282 (Reactome)
CDC25CArrowR-HSA-6798268 (Reactome)
CDC25CR-HSA-6802973 (Reactome)
CDKN1A geneR-HSA-6803388 (Reactome)
CDKN1A geneR-HSA-6803801 (Reactome)
CDKN1A mRNAArrowR-HSA-6803388 (Reactome)
CDKN1A mRNAR-HSA-6803403 (Reactome)
CDKN1A mRNAR-HSA-6803411 (Reactome)
CDKN1A,CDKN1BR-HSA-187934 (Reactome)
CDKN1A,CDKN1BR-HSA-69562 (Reactome)
CDKN1A,CDKN1Bmim-catalysisR-HSA-187934 (Reactome)
CDKN1A,CDKN1Bmim-catalysisR-HSA-69562 (Reactome)
CDKN1AArrowR-HSA-6803411 (Reactome)
CENPJR-HSA-6801666 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
ArrowR-HSA-187934 (Reactome)
Cyclin E:CDK2:CDKN1A,CDKN1BArrowR-HSA-69562 (Reactome)
E2F1 geneR-HSA-6798347 (Reactome)
E2F1 geneR-HSA-6798353 (Reactome)
E2F1ArrowR-HSA-6798353 (Reactome)
E2F4:(TFDP1,TFDP2):(RBL1,RBL2)R-HSA-6798282 (Reactome)
E2F7 GeneR-HSA-6798299 (Reactome)
E2F7 GeneR-HSA-6798304 (Reactome)
E2F7 homodimerArrowR-HSA-8952996 (Reactome)
E2F7,E2F8 dimers:E2F1 GeneArrowR-HSA-6798347 (Reactome)
E2F7,E2F8 dimers:E2F1 GeneTBarR-HSA-6798353 (Reactome)
E2F7,E2F8 dimersR-HSA-6798347 (Reactome)
E2F7:E2F8ArrowR-HSA-8953013 (Reactome)
E2F7ArrowR-HSA-6798299 (Reactome)
E2F7R-HSA-8952996 (Reactome)
E2F7R-HSA-8953013 (Reactome)
E2F8 homodimerArrowR-HSA-8953037 (Reactome)
E2F8R-HSA-8953013 (Reactome)
E2F8R-HSA-8953037 (Reactome)
EP300R-HSA-3215152 (Reactome)
GADD45A GeneR-HSA-3215144 (Reactome)
GADD45A GeneR-HSA-3215152 (Reactome)
GADD45A:AURKAArrowR-HSA-6791235 (Reactome)
GADD45A:PCNAArrowR-HSA-6791109 (Reactome)
GADD45AArrowR-HSA-3215144 (Reactome)
GADD45AR-HSA-6791109 (Reactome)
GADD45AR-HSA-6791235 (Reactome)
NPM1R-HSA-6801675 (Reactome)
PCBP4 GeneR-HSA-6803391 (Reactome)
PCBP4 GeneR-HSA-6803400 (Reactome)
PCBP4:CDKN1A mRNAArrowR-HSA-6803403 (Reactome)
PCBP4:CDKN1A mRNATBarR-HSA-6803411 (Reactome)
PCBP4ArrowR-HSA-6803400 (Reactome)
PCBP4R-HSA-6803403 (Reactome)
PCNA homotrimerR-HSA-6791109 (Reactome)
PLAGL1 GeneR-HSA-6803935 (Reactome)
PLAGL1 GeneR-HSA-6803946 (Reactome)
PLAGL1ArrowR-HSA-6803946 (Reactome)
PLK2 GeneR-HSA-6801637 (Reactome)
PLK2 GeneR-HSA-6801641 (Reactome)
PLK2ArrowR-HSA-6801637 (Reactome)
PLK2mim-catalysisR-HSA-6801666 (Reactome)
PLK2mim-catalysisR-HSA-6801675 (Reactome)
PLK3 GeneR-HSA-6802165 (Reactome)
PLK3 GeneR-HSA-6802170 (Reactome)
PLK3ArrowR-HSA-6802170 (Reactome)
PLK3mim-catalysisR-HSA-6802973 (Reactome)
PRMT1R-HSA-3215152 (Reactome)
R-HSA-187934 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (Guardavaccaro and Pagano, 2006).
R-HSA-3215144 (Reactome) Binding of TP53 (p53) to the p53 response element in the third intron of the GADD45A gene, together with chromatin modification mediated by TP53-associated proteins CARM1, PRMT1 and EP300, stimulates GADD45A transcription (An et al. 2004).
R-HSA-3215152 (Reactome) TP53, together with chromatin modifying enzymes EP300, PRMT1 and CARM1, binds the p53 response element in the third intron of the GADD45A gene (An et al. 2004).
R-HSA-6791109 (Reactome) GADD45A binds PCNA homotrimer (Smith et al. 1994, Hall et al. 1995, Sanchez et al. 2010). The consequences of this interaction are not clear. Binding to GADD45A may negatively regulate PCNA-mediated DNA synthesis during S phase of the cell cycle or it may promote PCNA-mediated DNA repair synthesis (Smith et al. 1994, Kim et al. 2013).
R-HSA-6791235 (Reactome) GADD45A binds Aurora-A protein kinase (AURKA). GADD45A inhibits the kinase activity of AURKA and AURKA-induced centrosome amplification, thus interfering with the G2/M transition (Shao et al. 2006, Sanchez et al. 2010).
R-HSA-6791363 (Reactome) TP53 (p53) stimulates transcription of the ARID3A gene upon binding to the p53 response element in the second intron of the ARID3A gene (Ma et al. 2003). ARID3A is implicated as both a positive and a negative cell cycle regulator. It interacts with E2F1 and stimulates E2F1 transcriptional activity (Suzuki et al. 1998, Peeper et al. 2002). It may also cooperate with TP53 in the activation of CDKN1A (p21) transcription (Lestari et al. 2012).
R-HSA-6791387 (Reactome) TP53 (p53) binds the p53 response element located in the second intron of the ARID3A gene (Ma et al. 2003).
R-HSA-6798020 (Reactome) TP53 (p53) binds the p53 response element in the promoter of the BTG2 gene (Duriez et al. 2002).
R-HSA-6798031 (Reactome) Upon binding to the p53 response element in the promoter of the BTG2 gene, TP53 induces expression of BTG2 (Rouault et al. 1996, Duriez et al. 2002).
R-HSA-6798044 (Reactome) BTG2, through its conserved BTG domain, binds catalytic subunits CNOT7 and CNOT8 of the CCR4-NOT complex and promotes mRNA deadenylation activity of the CCR4-NOT (Rouault et al. 1998, Mauxion et al. 2008, Doidge et al. 2012). The interaction with the CCR4-NOT is needed for the antiproliferative activity of BTG2 (Horiuchi et al. 2009, Doidge et al. 2012, Ezzeddine et al. 2012).
R-HSA-6798268 (Reactome) Binding of TP53 and the E2F4 repressor complex to the promoter of the CDC25C gene results in the inhibition of CDC25C transcription, an important step in the maintenance of the G2 cell cycle checkpoint (St. Clair et al. 2004, Benson et al. 2014).
R-HSA-6798282 (Reactome) The promoter of the CDC25C gene contains p53 response elements as well as E2F binding sites and can bind both TP53 (St Clair et al. 2004) and E2F4 (Benson et al. 2014). E2F4 transcription repressor complex consists of E2F4, a transcriptional co-factor TFDP1 (DP1) or TFDP2 (DP2), and a retinoblastoma family protein RBL1 (p107) or RBL2 (p130). The CDK inhibitor p21 (CDKN1A), induced by TP53, positively affects E2F4 recruitment to the CDC25C promoter, probably by upregulating RBL2 (Helmbold et al. 2009, Benson et al. 2014).
R-HSA-6798299 (Reactome) Binding of TP53 (p53) to the p53 response element in the promoter of the E2F7 gene stimulates E2F7 transcription (Carvajal et al. 2012, Aksoy et al. 2012).
R-HSA-6798304 (Reactome) TP53 (p53) binds the p53 response element in the promoter of the E2F7 gene (Carvajal et al. 2012, Aksoy et al. 2012).
R-HSA-6798347 (Reactome) E2F7 binds to E2F sites in the promoter of the E2F1 gene to inhibit its expression (Di Stefano et al. 2003, Carvajal et al. 2012, Aksoy et al. 2012). Besides E2F7 homodimers, heterodimers of E2F7 and E2F8, as well as E2F8 homodimers, can also bind to the promoter of the E2F1 gene to inhibit its transcription (Li et al. 2008, Zalmas et al. 2008).
R-HSA-6798353 (Reactome) Upon binding to E2F elements in the promoter of the E2F1 gene, E2F7 represses transcription of E2F1 (Di Stefano et al. 2003, Li et al. 2008, Zalmas et al. 2008, Carvajal et al. 2012). E2F1 transcription is also directly repressed by E2F8. E2F7 and E2F8 bind to the E2F1 gene promoter as homo- or heterodimers (Li et al. 2008, Zalmas et al. 2008). E2F7- and E2F8-mediated repression of E2F1 transcription is an important step in the DNA damage induced cell cycle arrest (Zalmas et al. 2008). E2F8-mediated repression of the E2F1 gene is involved in the polyploidization of hepatocytes during liver development (Pandit et al. 2012). Loss of E2F7 and E2F8 triggers apoptosis via induction of E2F1 in response to stress (Li et al. 2008, Thurlings et al. 2016).
R-HSA-6801637 (Reactome) Binding of TP53 to p53 binding site(s) in the promoter of the PLK2 gene stimulates PLK2 transcription. PLK2 may be involved in prevention of the mitotic catastrophe after spindle damage (Burns et al. 2003). PLK2 is frequently transcriptionally silenced through promoter methylation in B-cell malignancies (Syed et al. 2006).
R-HSA-6801641 (Reactome) TP53 (p53) can bind three p53 binding sites in the promoter of the PLK2 gene (Burns et al. 2003).
R-HSA-6801666 (Reactome) PLK2 phosphorylates centrosome protein CENPJ (CPAP) on serine residues S589 and S585, which is a prerequisite for procentriole formation and centrosome duplication (Chang et al. 2010).
R-HSA-6801675 (Reactome) PLK2 phosphorylates NPM1 (nucleophosmin) on serine residue S4, which may be necessary to trigger centrosome duplication (Krause and Hoffmann 2010).
R-HSA-6802165 (Reactome) TP53 (p53) binds the p53 response element in the promoter of the PLK3 (Polo-like kinase 3) gene (Jen and Cheung 2005).
R-HSA-6802170 (Reactome) Binding of TP53 (p53) to the p53 response element in the promoter of the PLK3 gene stimulates PLK3 transcription (Jen and Cheung 2005).
R-HSA-6802973 (Reactome) PLK3 phosphorylates CDC25C at serine residue S191 within the nuclear export signal (NES). Phosphorylation of CDC25C at S191 promotes nuclear localization of CDC25C, probably by masking the NES. Nuclear accumulation of CDC25C may be important for coordination of M phase events (Bahassi et al. 2004).
R-HSA-6803388 (Reactome) Binding of TP53 (p53) to its response elements in the promoter of the CDKN1A (p21) gene stimulates CDKN1A transcription (El-Deiry et al. 1993). Binding of ZNF385A (HZF) to the DNA binding domain of TP53 facilitates CDKN1A induction and the consequent cell cycle arrest (Das et al. 2007).
R-HSA-6803391 (Reactome) TP53 (p53) binds two p53 response elements in the promoter of the PCBP4 (MCG10) gene (Zhu and Chen 2000).
R-HSA-6803400 (Reactome) Binding of TP53 (p53) to two p53 response elements in the promoter of the PCBP4 (MCG10) gene stimulates PCBP4 transcription. PCBP4 has three K homology (KH) domains involved in RNA binding that can interact with a poly(C) sequence. PCBP4 binding destabilizes its targets, including CDKN1A (p21), thus favouring p53-dependent apoptosis over cell cycle arrest (Zhu and Chen 2000).
R-HSA-6803403 (Reactome) PCBP4 binds the 3'-UTR of the CDKN1A (p21) mRNA and reduces its stability (Scoumanne et al. 2011).
R-HSA-6803411 (Reactome) PCBP4 binding to the 3'-UTR of the CDKN1A (p21) mRNA reduces half-life of the CDKN1A mRNA and the amount of CDKN1A protein. Upon DNA damage, TP53-mediated induction of CDKN1A is rapid, while the induction of PCBP4 is more gradual. It is hypothesized that, under prolonged stress, PCBP4-mediated down-regulation of CDKN1A may switch from G1 cell cycle arrest to G2 arrest, which may precede apoptosis (Scoumanne et al. 2011).
R-HSA-6803801 (Reactome) TP53 (p53) binds at least two p53 response elements in the promoter of the CDKN1A (p21, WAF1) gene (El-Deiry et al. 1993, Espinosa et al. 2003). Formation of the complex of TP53 and ZNF385A (HZF) facilitates binding of TP53 to the CDKN1A promoter (Das et al. 2007).
R-HSA-6803858 (Reactome) TP53 (p53) binds the p53 response element in the promoter region of the SFN (14-3-3 sigma) gene (Hermeking et al. 1997). Interaction between ZNF385A (HZF) and TP53 facilitates TP53 binding to the promoter of the SFN gene (Das et al. 2007).
R-HSA-6803871 (Reactome) Binding of TP53 (p53) to the p53 response element in the promoter region of the SFN (14-3-3 sigma) gene stimulates SFN transcription. SFN expression triggers G2 arrest in response to genotoxic agents by sequestering proteins involved in cell cycle progression in the cytosol (Hermeking et al. 1997, Chan et al. 1999). Formation of the complex of TP53 and ZNF385A (HZF) facilitates TP53-mediated induction of SFN3 (Das et al. 2007).
R-HSA-6803875 (Reactome) SFN (14-3-3-sigma) dimer binds the complex of CCNB1 (cyclin B1) and CDK1 (Cdc2) in the cytosol and prevents the translocation of the CCNB1:CDK1 complex into the nucleus. This induces G2 cell cycle arrest as nuclear localization of the CCNB1:CDK1 complex is necessary for phosphorylation of nuclear target proteins that are needed for the G2/M transition (Chan et al. 1999).
R-HSA-6803890 (Reactome) SFN functions as a homodimer (Verdoodt et al. 2006).
R-HSA-6803892 (Reactome) SFN (14-3-3-sigma) dimer forms a complex with BAX. Binding of SFN to BAX prevents BAX translocation from cytosol to mitochondria, thus inhibiting cytochrome C release and apoptosis. SFN therefore promotes G2 cell cycle arrest while simultaneously preventing apoptosis (Samuel et al. 2001).
R-HSA-6803914 (Reactome) TP53 (p53) binds to the p53 response element in the second intron of the RGCC (RGC32) gene (Saigusa et al. 2007).
R-HSA-6803917 (Reactome) Binding of TP53 (p53) to the p53 response element in the second intron of the RGCC (RGC32) gene stimulates RGCC transcription. RGCC is implicated in cell cycle regulation, but the mechanism is unknown. RGCC can associate with PLK1, but the biological significance of this interaction has not been elucidated. The RGCC gene is frequently deleted and down-regulated in glioma (Saigusa et al. 2007). However, RGCC overexpression has been reported in several different tumor types (Fosbrink et al. 2005).
R-HSA-6803935 (Reactome) TP53 binds the p53 response element in the promoter of the PLAGL1 (ZAC1) gene (Rozenfeld-Granot et al. 2002).
R-HSA-6803946 (Reactome) Binding of TP53 (p53) to the p53 response element in the promoter of the PLAGL1 (ZAC1) gene stimulates PLAGL1 transcription (Rozenfeld-Granot et al. 2002). PLAGL1 is a zinc finger protein implicated in transcriptional regulation. PLAGL1 expression correlates with both cell cycle arrest and apoptosis (Spengler et al. 1997) and is frequently lost in cancer (Varrault et al. 1998). The mechanism of PLAGL1 action requires further elucidation.
R-HSA-69562 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF (Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2.
R-HSA-8952996 (Reactome) E2F7 forms homodimers (Di Stefano et al. 2003, Logan et al. 2004). While E2F7 also forms heterodimers with E2F8, co-immunoprecipitation experiments suggest that E2F7 has higher affinity for itself than for E2F8 (Li et al. 2008)
R-HSA-8953013 (Reactome) E2F7 forms heterodimers with E2F8 (Li et al. 2008, Zalmas et al. 2008).
R-HSA-8953037 (Reactome) E2F8 forms homodimers (Maiti et al. 2005, Li et al. 2008). E2F8 also forms heterodimers with E2F7 and co-immunoprecipitation experiments suggest that E2F8 has higher affinity for E2F7 than for itself (Zalmas et al. 2008, Li et al. 2008).
RGCC GeneR-HSA-6803914 (Reactome)
RGCC GeneR-HSA-6803917 (Reactome)
RGCCArrowR-HSA-6803917 (Reactome)
SFN Dimer:BAXArrowR-HSA-6803892 (Reactome)
SFN Dimer:CCNB1:CDK1ArrowR-HSA-6803875 (Reactome)
SFN DimerArrowR-HSA-6803890 (Reactome)
SFN DimerR-HSA-6803875 (Reactome)
SFN DimerR-HSA-6803892 (Reactome)
SFN GeneR-HSA-6803858 (Reactome)
SFN GeneR-HSA-6803871 (Reactome)
SFNArrowR-HSA-6803871 (Reactome)
SFNR-HSA-6803890 (Reactome)
p-S15,S20-TP53

Tetramer:ARID3A

Gene
ArrowR-HSA-6791363 (Reactome)
p-S15,S20-TP53

Tetramer:ARID3A

Gene
ArrowR-HSA-6791387 (Reactome)
p-S15,S20-TP53 Tetramer:BTG2 GeneArrowR-HSA-6798020 (Reactome)
p-S15,S20-TP53 Tetramer:BTG2 GeneArrowR-HSA-6798031 (Reactome)
p-S15,S20-TP53 Tetramer:E2F4:(TFDP1,TFDP2):(RBL1,RBL2):CDC25C GeneArrowR-HSA-6798282 (Reactome)
p-S15,S20-TP53 Tetramer:E2F4:(TFDP1,TFDP2):(RBL1,RBL2):CDC25C GeneTBarR-HSA-6798268 (Reactome)
p-S15,S20-TP53 Tetramer:E2F7 GeneArrowR-HSA-6798299 (Reactome)
p-S15,S20-TP53 Tetramer:E2F7 GeneArrowR-HSA-6798304 (Reactome)
p-S15,S20-TP53 Tetramer:PCBP4 GeneArrowR-HSA-6803391 (Reactome)
p-S15,S20-TP53 Tetramer:PCBP4 GeneArrowR-HSA-6803400 (Reactome)
p-S15,S20-TP53

Tetramer:PLAGL1

Gene
ArrowR-HSA-6803935 (Reactome)
p-S15,S20-TP53

Tetramer:PLAGL1

Gene
ArrowR-HSA-6803946 (Reactome)
p-S15,S20-TP53 Tetramer:PLK2 GeneArrowR-HSA-6801637 (Reactome)
p-S15,S20-TP53 Tetramer:PLK2 GeneArrowR-HSA-6801641 (Reactome)
p-S15,S20-TP53 Tetramer:PLK3 GeneArrowR-HSA-6802165 (Reactome)
p-S15,S20-TP53 Tetramer:PLK3 GeneArrowR-HSA-6802170 (Reactome)
p-S15,S20-TP53 Tetramer:RGCC GeneArrowR-HSA-6803914 (Reactome)
p-S15,S20-TP53 Tetramer:RGCC GeneArrowR-HSA-6803917 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385A:CDKN1A GeneArrowR-HSA-6803388 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385A:CDKN1A GeneArrowR-HSA-6803801 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385A:SFN GeneArrowR-HSA-6803858 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385A:SFN GeneArrowR-HSA-6803871 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AR-HSA-6803801 (Reactome)
p-S15,S20-TP53 Tetramer:ZNF385AR-HSA-6803858 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-3215152 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6791387 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6798020 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6798282 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6798304 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6801641 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6802165 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6803391 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6803914 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6803935 (Reactome)
p-S15,S20-TP53:EP300:PRMT1:CARM1:GADD45A GeneArrowR-HSA-3215144 (Reactome)
p-S15,S20-TP53:EP300:PRMT1:CARM1:GADD45A GeneArrowR-HSA-3215152 (Reactome)
p-S191-CDC25CArrowR-HSA-6802973 (Reactome)
p-S4-NPM1ArrowR-HSA-6801675 (Reactome)
p-S589,S595-CENPJArrowR-HSA-6801666 (Reactome)

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