TP53 Regulates Transcription of Cell Cycle Genes (Homo sapiens)

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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>

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

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  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
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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 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 homotrimerComplex