Oxidative Stress Induced Senescence (Homo sapiens)

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3, 5, 7, 9, 11...10, 12, 48, 110, 131901201235957, 66, 70, 12518143, 5853, 2312356, 7214, 495726, 39, 455783, 1111, 46, 65, 91, 1099, 6311944, 68, 70, 12529271231238029, 44, 594, 28, 64, 76, 96...25, 74, 10069, 1247, 32, 36, 42, 53...11, 3733, 80, 85, 9911933, 8390, 1202744, 68cytosolnucleoplasmmitochondrial matrixMitotic G1-G1/SphasesRBBP4 HIST3H2BB p-T180,Y182-MAPK11 HIST1H2AJ INK4JUNphospho-p38MAPK:p-T-182-MAPKAPK5IFNB1CBX8 H2AFX CDK4 Me3K-28-HIST1H3A p-MAPK8/9/10RNF2 KDM6Bp38 MAPK:MAPKAPK2/3CDKN2D EIF2C4 E2F1 CDKN2B p-S166,S188-MDM2 BMI1 PHC2 p38 MAPK:MAPKAPK5CBX2 p-S166,S188-MDM2 p-T185,Y187-MAPK1 p-S166,S188-MDM2dimer,p-S166,S188-MDM2,MDM4:TP53PRC1.4p-S166,S188-MDM2 ATPMDM4 CBX4 ADPHIST2H2AA3 TFDP1 CDKN2D TP53 ATPp-T221,Y223-MAPK10 H2AFB1 HIST2H2BE HIST1H4 TNIK gene miR-24-1 SUCCAMAPK11 HIST1H2BJ H2AFX p-MAPK8/9/10PHC1 MAP3K5:TXNH2AFX Senescence-Associated Secretory Phenotype (SASP)p-S37-TP53 TetramerHIST1H2BD CDKN2A gene p-S63,S73-JUNHIST1H2BO p14-ARF mRNA CDKN2A geneUBB(1-76) HIST3H2BB HIST1H2BL SCMH1-2 Intrinsic Pathwayfor ApoptosisHIST1H2AD HIST1H2AD p-S189,T193-MAP2K3 E2F1 TXN Fe2+PHC1 TNRC6C p16-INK4a/p14-ARFmRNAMAPK8/9/10EED GeneHIST1H2BC p14-ARF mRNAp-S166,S188-MDM2 p-T,Y-MAPK8 TFDP2 HIST2H2AC p-S63,S73-JUN p-S257,T261-MAP2K4 HIST1H2AC E2F2 KDM6B GeneMe3K-28-HIST2H3A UBB(77-152) p-T180,Y182-MAPK11 PHC2 MINK1/TNIK genesMAP2K4MKK3/MKK6EIF2C3 TFDP2 CDKN2A gene HIST2H2AA3 TNRC6C MINK1/TNIKMAPK10 Oncogene InducedSenescenceHIST2H3A RBBP7 H2AFZ ATPMAPKAPK3 p-T180,Y182-MAPK14 p16-INK4A mRNA MAPK14 p-S207,T211-MAP2K6 CBX2 Me3K-28-H3F3A E2F2 CBX4 MAP2K6 HIST1H2BJ HIST1H4 MAP3K5 RNF2 E2F3 ADPHIST1H2BH SUZ12 KDM6B HIST2H2BE HIST1H2BK PHC3 SCMH1-2 PHC3 Cell CycleCheckpointsp-T180,Y182-MAPK11 UBC(305-380) phospho-p38 MAPK:MAPKAPK5p-T180,Y182-MAPK14 CDK6 E2F1 p-S166,S188-MDM2dimer,p-S166,S188-MDM2:MDM4MOV10 RBBP7TFDP1 HIST1H2BB E2F1 ADPMDM4 HIST1H2AC H2BFS H2AFJ HIST1H2AB phospho-MAPKp38:p-MAPKAPK3PHC2 HIST1H2BA E2F2 phospho-p38 MAPK:MAPKAPK2/3H2AFZ p16-INK4a/p14-ARFmRNA: miR-24NonendonucleolyticRISCp-T183,Y185-MAPK9 MAPKAPK2 HIST3H2BB H2AFJ KDM6B Gene EZH2Gene:E2F1/2/3:DP1/2p16-INK4ap16-INK4a CBX6 p-T180,Y182-MAPK14 HIST1H2BL BMI1 p-T180,Y182-MAPK14 PHC1 ATPMAP3K5UBA52(1-76) p-S207,T211-MAP2K6 EZH2 p-S,2T-MAPKAPK3 PRC2 (EZH2) CoreTNIK p-S189,T193-MAP2K3 p-S271,T275-MAP2K7 ADPH2BFS HIST1H2AC HIST2H2AC p16-INK4A mRNAADPHIST1H4 EIF2C1 HIST2H2BE ATPHIST1H2AD CBX6 HIST1H2BM AdoMetHIST1H2BO MINK1 HIST1H2BM p-T,Y MAPK dimersCDKN2AGene:NucleosomeCDKN2B miR-24-1 RING1 p-T325,T331,S362,S374-FOS UBC(533-608) HIST1H2BH DNA Damage/TelomereStress InducedSenescenceCDKN2C CBX8 ATPHIST1H2BN UBC(381-456) HIST1H2AB UBC(153-228) HIST1H2BN HIST1H2BN AdoHcyEED p-T180,Y182-MAPK11 p-T180,Y182-MAPK14 E2F3 H2BFS ADPUBC(457-532) CDK6 p-S-BMI1 CDKN2AGene:H3K27Me3-Nucleosome:PRC1.4EEDp-T325,T331,S362,S374-FOS p14-ARFH2AFV PolyUb-TP53 p14-ARF HIST1H2AJ H3F3A MDM4 p14-ARF p-2S-cJUN:p-2S,2T-cFOSMAPKAPK2 UbRING1 p-p38MAPK:p-MAPKAPK2/3H2AFJ ATPHIST1H2BK p-T180,Y182-MAPK11 SUZ12 Gene SUZ12 GenemiR-24-2 SCMH1-2 MAPKAPK3 PHC3 TNRC6B MOV10 H2AFB1 CDK4,CDK6:INK4TFDP1 EZH2 Gene CBX6 p16-INK4A mRNA H2AFV TFDP2 EIF2C1 MAPK8 p-MKK3/p-MKK6EIF2C4 HIST1H2BB RNF2 HIST1H2BM ADPHIST1H2BO HIST1H2BD ROSMINK1 gene MAPK9 SUZ12Gene:E2F1/2/3:DP1/2TNRC6B RING1 p-S,2T-MAPKAPK3 UBC(77-152) HIST1H2BC FOSHIST1H2BD EED Gene p-T202,Y204-MAPK3 MDM4 CDK4,CDK6UBC(609-684) TP53 TetramerHIST1H2BL Me3K-28-HIST2H3A p-S37-TP53 p-T221,Y223-MAPK10 ATPE2F3 TP53 p-T222,S272,T334-MAPKAPK2 MAPKAPK5 p-2S-cJUN:p-2S,2T-cFOS:KDM6B GeneCDKN2C RBBP4HIST2H2AC p-PRC1.4 complexp-MAP2K4/p-MAP2K7p-T183,Y185-MAPK9 E2F3 HIST1H2BH Me3K-28-H3F3A p-T,Y-MAPK8 p-T182-MAPKAPK5 miR-24NonendonucleolyticRISCHIST1H2AJ ADPp16-INK4a TP53 p14-ARF mRNA E2F2 CBX2 Fe2+ ADPEIF2C3 TFDP1,TFDP2:E2F1,E2F2,E2F3H2AFB1 Me3K-28-HIST1H3A Oncogenic MAPKsignalingCDKN2AGene:H3K27Me3-NucleosomeMAP2K3 p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4HIST1H2BJ p-MKK3/p-MKK62xHC-TXNSUZ12MAPK11 UBC(229-304) 2OGTNRC6A PolyUb-TP53 TetramerATPH2AFZ HIST1H2BK HIST2H2AA3 miR-24-2 HIST1H2BA H2AFV UBC(1-76) ATPEZH2CDK4 CBX4 CDKN2A gene HIST1H2BC p-S257,T261-MAP2K4TNRC6A p-T325,T331,S362,S374-FOSADPHIST1H2AB TFDP2 MAPK14 UBB(153-228) HIST1H3A ADPMAPKAPK5 MAP4K4 EEDGene:E2F1/2/3:DP1/2KDM6B:Fe2+p-S63,S73-JUN EZH2 Genep14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53RPS27A(1-76) ATPMAP4K4 gene CBX8 HIST1H2BA TFDP1 HIST1H2BB 57, 66, 70, 1258, 18, 31, 112, 12190, 120294958, 77, 10244, 682712334, 43, 51, 105, 117...21, 104, 106, 1076612313, 22, 30, 41, 50...2, 6, 15, 19, 20, 24...4, 17, 35, 38, 47...996616, 101, 129


Description

Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).


MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.<p>
MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).<p>
Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997). <p>
Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16-INK4A and p14-ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14-ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14-ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16-INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).<p>
p16-INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14-ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007). View original pathway at:Reactome.</div>

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Reactome-Converter 
Pathway is converted from Reactome ID: 2559580
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Reactome version: 61
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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  66. Baek KH, Ryeom S.; ''Detection of Oncogene-Induced Senescence In Vivo.''; PubMed Europe PMC Scholia
  67. Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y.; ''pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene.''; PubMed Europe PMC Scholia
  68. 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 Scholia
  69. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z.; ''Mdm2 association with p53 targets its ubiquitination.''; PubMed Europe PMC Scholia
  70. Takekawa M, Tatebayashi K, Saito H.; ''Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases.''; PubMed Europe PMC Scholia
  71. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D.; ''RAS oncogenes: weaving a tumorigenic web.''; PubMed Europe PMC Scholia
  72. Mizukami Y, Yoshioka K, Morimoto S, Yoshida Ki.; ''A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.''; PubMed Europe PMC Scholia
  73. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y.; ''Enhanced phosphorylation of p53 by ATM in response to DNA damage.''; PubMed Europe PMC Scholia
  74. Okazaki K, Sagata N.; ''The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells.''; PubMed Europe PMC Scholia
  75. Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenführ M, Maertens G, Banck M, Zhou MM, Walsh MJ, Peters G, Gil J.; ''Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.''; PubMed Europe PMC Scholia
  76. Takahashi A, Imai Y, Yamakoshi K, Kuninaka S, Ohtani N, Yoshimoto S, Hori S, Tachibana M, Anderton E, Takeuchi T, Shinkai Y, Peters G, Saya H, Hara E.; ''DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells.''; PubMed Europe PMC Scholia
  77. Nicke B, Bastien J, Khanna SJ, Warne PH, Cowling V, Cook SJ, Peters G, Delpuech O, Schulze A, Berns K, Mullenders J, Beijersbergen RL, Bernards R, Ganesan TS, Downward J, Hancock DC.; ''Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells.''; PubMed Europe PMC Scholia
  78. Cobrinik D.; ''Pocket proteins and cell cycle control.''; PubMed Europe PMC Scholia
  79. Wu X, Bayle JH, Olson D, Levine AJ.; ''The p53-mdm-2 autoregulatory feedback loop.''; PubMed Europe PMC Scholia
  80. Glover JN, Harrison SC.; ''Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA.''; PubMed Europe PMC Scholia
  81. Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T, Matsumoto K, Takeuchi O, Akira S.; ''Essential function for the kinase TAK1 in innate and adaptive immune responses.''; PubMed Europe PMC Scholia
  82. Erickson S, Sangfelt O, Heyman M, Castro J, Einhorn S, Grandér D.; ''Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence.''; PubMed Europe PMC Scholia
  83. 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 Scholia
  84. Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM.; ''Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.''; PubMed Europe PMC Scholia
  85. Lee JH, Paull TT.; ''ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.''; PubMed Europe PMC Scholia
  86. Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMed Europe PMC Scholia
  87. Cao R, Zhang Y.; ''SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex.''; PubMed Europe PMC Scholia
  88. Lukas SM, Kroe RR, Wildeson J, Peet GW, Frego L, Davidson W, Ingraham RH, Pargellis CA, Labadia ME, Werneburg BG.; ''Catalysis and function of the p38 alpha.MK2a signaling complex.''; PubMed Europe PMC Scholia
  89. Yu TW, Anderson D.; ''Reactive oxygen species-induced DNA damage and its modification: a chemical investigation.''; PubMed Europe PMC Scholia
  90. Zhang H, Cohen SN.; ''Smurf2 up-regulation activates telomere-dependent senescence.''; PubMed Europe PMC Scholia
  91. Yang D, Elner SG, Bian ZM, Till GO, Petty HR, Elner VM.; ''Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells.''; PubMed Europe PMC Scholia
  92. Harley CB, Futcher AB, Greider CW.; ''Telomeres shorten during ageing of human fibroblasts.''; PubMed Europe PMC Scholia
  93. Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P.; ''Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2.''; PubMed Europe PMC Scholia
  94. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G.; ''The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing.''; PubMed Europe PMC Scholia
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  96. Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B.; ''Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53.''; PubMed Europe PMC Scholia
  97. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y.; ''Role of histone H3 lysine 27 methylation in Polycomb-group silencing.''; PubMed Europe PMC Scholia
  98. Moiseeva O, Bourdeau V, Roux A, Deschênes-Simard X, Ferbeyre G.; ''Mitochondrial dysfunction contributes to oncogene-induced senescence.''; PubMed Europe PMC Scholia
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  100. Chen J, Marechal V, Levine AJ.; ''Mapping of the p53 and mdm-2 interaction domains.''; PubMed Europe PMC Scholia
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  102. Hartupee J, Li X, Hamilton T.; ''Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1.''; PubMed Europe PMC Scholia
  103. Nelson ML, Kang HS, Lee GM, Blaszczak AG, Lau DK, McIntosh LP, Graves BJ.; ''Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP.''; PubMed Europe PMC Scholia
  104. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T.; ''Control of human telomere length by TRF1 and TRF2.''; PubMed Europe PMC Scholia
  105. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D.; ''Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein.''; PubMed Europe PMC Scholia
  106. Raingeaud J, Whitmarsh AJ, Barrett T, Dérijard B, Davis RJ.; ''MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway.''; PubMed Europe PMC Scholia
  107. 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 Scholia
  108. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ.; ''The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.''; PubMed Europe PMC Scholia
  109. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K.; ''EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.''; PubMed Europe PMC Scholia
  110. Maki CG.; ''Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2.''; PubMed Europe PMC Scholia
  111. Connelly KE, Dykhuizen EC.; ''Compositional and functional diversity of canonical PRC1 complexes in mammals.''; PubMed Europe PMC Scholia
  112. Yang BS, Hauser CA, Henkel G, Colman MS, Van Beveren C, Stacey KJ, Hume DA, Maki RA, Ostrowski MC.; ''Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.''; PubMed Europe PMC Scholia
  113. 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 Scholia
  114. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J.; ''Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.''; PubMed Europe PMC Scholia
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  116. Raivich G.; ''c-Jun expression, activation and function in neural cell death, inflammation and repair.''; PubMed Europe PMC Scholia
  117. Dennler S, Prunier C, Ferrand N, Gauthier JM, Atfi A.; ''c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity.''; PubMed Europe PMC Scholia
  118. Parisi T, Pollice A, Di Cristofano A, Calabrò V, La Mantia G.; ''Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.''; PubMed Europe PMC Scholia
  119. Young AR, Narita M.; ''SASP reflects senescence.''; PubMed Europe PMC Scholia
  120. 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 Scholia
  121. Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J.; ''Molecular interpretation of ERK signal duration by immediate early gene products.''; PubMed Europe PMC Scholia
  122. Seidel JJ, Graves BJ.; ''An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors.''; PubMed Europe PMC Scholia
  123. 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 Scholia
  124. Lindström MS, Klangby U, Inoue R, Pisa P, Wiman KG, Asker CE.; ''Immunolocalization of human p14(ARF) to the granular component of the interphase nucleolus.''; PubMed Europe PMC Scholia
  125. Lavoie H, Therrien M.; ''Regulation of RAF protein kinases in ERK signalling.''; PubMed Europe PMC Scholia
  126. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD.; ''Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.''; PubMed Europe PMC Scholia
  127. Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J.; ''Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage.''; PubMed Europe PMC Scholia
  128. Clifton AD, Young PR, Cohen P.; ''A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress.''; PubMed Europe PMC Scholia
  129. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, Xie C, Chen J, Deng Q, Yamout M, Dong MQ, Frangou CG, Yates JR, Wright PE, Han J.; ''PRAK is essential for ras-induced senescence and tumor suppression.''; PubMed Europe PMC Scholia
  130. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed Europe PMC Scholia
  131. ter Haar E, Prabhakar P, Liu X, Lepre C.; ''Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer.''; PubMed Europe PMC Scholia
  132. Serrano M, Hannon GJ, Beach D.; ''A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.''; PubMed Europe PMC Scholia
  133. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH.; ''Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.''; PubMed Europe PMC Scholia
  134. Atwood AA, Sealy LJ.; ''C/EBPβ's role in determining Ras-induced senescence or transformation.''; PubMed Europe PMC Scholia
  135. Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K.; ''The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence.''; PubMed Europe PMC Scholia
  136. Sadasivam S, DeCaprio JA.; ''The DREAM complex: master coordinator of cell cycle-dependent gene expression.''; PubMed Europe PMC Scholia
  137. Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut P, Luo W, Chicas A, Lee CS, Kogan SC, Lowe SW.; ''Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.''; PubMed Europe PMC Scholia
  138. Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ.; ''Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine.''; PubMed Europe PMC Scholia
  139. Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR.; ''MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1.''; PubMed Europe PMC Scholia
  140. Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T.; ''p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2.''; PubMed Europe PMC Scholia
  141. Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E.; ''Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.''; PubMed Europe PMC Scholia
  142. Ainbinder E, Bergelson S, Pinkus R, Daniel V.; ''Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agents.''; PubMed Europe PMC Scholia
  143. 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 Scholia
  144. Weinmann AS, Bartley SM, Zhang T, Zhang MQ, Farnham PJ.; ''Use of chromatin immunoprecipitation to clone novel E2F target promoters.''; PubMed Europe PMC Scholia
  145. Bailly S, Fay M, Israël N, Gougerot-Pocidalo MA.; ''The transcription factor AP-1 binds to the human interleukin 1 alpha promoter.''; PubMed Europe PMC Scholia
  146. Deacon K, Blank JL.; ''Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo.''; PubMed Europe PMC Scholia
  147. 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 Scholia
  148. Quelle DE, Zindy F, Ashmun RA, Sherr CJ.; ''Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.''; PubMed Europe PMC Scholia
  149. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114859view16:36, 25 January 2021ReactomeTeamReactome version 75
113305view11:37, 2 November 2020ReactomeTeamReactome version 74
112517view15:47, 9 October 2020ReactomeTeamReactome version 73
101429view11:30, 1 November 2018ReactomeTeamreactome version 66
100967view21:08, 31 October 2018ReactomeTeamreactome version 65
100504view19:42, 31 October 2018ReactomeTeamreactome version 64
100050view16:25, 31 October 2018ReactomeTeamreactome version 63
99602view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94042view13:53, 16 August 2017ReactomeTeamreactome version 61
93667view11:30, 9 August 2017ReactomeTeamreactome version 61
88083view09:11, 26 July 2016RyanmillerOntology Term : 'oxidative stress response pathway' added !
88082view09:11, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86788view09:26, 11 July 2016ReactomeTeamreactome version 56
83222view10:25, 18 November 2015ReactomeTeamVersion54
81616view13:09, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2OGMetaboliteCHEBI:30915 (ChEBI)
2xHC-TXNProteinP10599 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BMI1 ProteinP35226 (Uniprot-TrEMBL)
CBX2 ProteinQ14781 (Uniprot-TrEMBL)
CBX4 ProteinO00257 (Uniprot-TrEMBL)
CBX6 ProteinO95503 (Uniprot-TrEMBL)
CBX8 ProteinQ9HC52 (Uniprot-TrEMBL)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDK4,CDK6:INK4ComplexR-HSA-182579 (Reactome)
CDK4,CDK6ComplexR-HSA-69209 (Reactome)
CDK6 ProteinQ00534 (Uniprot-TrEMBL)
CDKN2A Gene:H3K27Me3-Nucleosome:PRC1.4ComplexR-HSA-3229098 (Reactome)
CDKN2A Gene:H3K27Me3-NucleosomeComplexR-HSA-3222570 (Reactome)
CDKN2A Gene:NucleosomeComplexR-HSA-3222592 (Reactome)
CDKN2A gene ProteinENSG00000147889 (Ensembl)
CDKN2A geneGeneProductENSG00000147889 (Ensembl)
CDKN2B ProteinP42772 (Uniprot-TrEMBL)
CDKN2C ProteinP42773 (Uniprot-TrEMBL)
CDKN2D ProteinP55273 (Uniprot-TrEMBL)
Cell Cycle CheckpointsPathwayR-HSA-69620 (Reactome) A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.

Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs.

The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear.

DNA Damage/Telomere

Stress Induced

Senescence
PathwayR-HSA-2559586 (Reactome) Reactive oxygen species (ROS), whose concentration increases in senescent cells due to oncogenic RAS-induced mitochondrial dysfunction (Moiseeva et al. 2009) or due to environmental stress, cause DNA damage in the form of double strand breaks (DSBs) (Yu and Anderson 1997). In addition, persistent cell division fueled by oncogenic signaling leads to replicative exhaustion, manifested in critically short telomeres (Harley et al. 1990, Hastie et al. 1990). Shortened telomeres are no longer able to bind the protective shelterin complex (Smogorzewska et al. 2000, de Lange 2005) and are recognized as damaged DNA.

The evolutionarily conserved MRN complex, consisting of MRE11A (MRE11), RAD50 and NBN (NBS1) subunits, binds DSBs (Lee and Paull 2005) and shortened telomeres that are no longer protected by shelterin (Wu et al. 2007). Once bound to the DNA, the MRN complex recruits and activates ATM kinase (Lee and Paull 2005, Wu et al. 2007), leading to phosphorylation of ATM targets, including TP53 (p53) (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998). TP53, phosphorylated on serine S15 by ATM, binds the CDKN1A (also known as p21, CIP1 or WAF1) promoter and induces CDKN1A transcription (El-Deiry et al. 1993, Karlseder et al. 1999). CDKN1A inhibits the activity of CDK2, leading to G1/S cell cycle arrest (Harper et al. 1993, El-Deiry et al. 1993).

SMURF2 is upregulated in response to telomere attrition in human fibroblasts and induces senecscent phenotype through RB1 and TP53, independently of its role in TGF-beta-1 signaling (Zhang and Cohen 2004). The exact mechanism of SMURF2 involvement is senescence has not been elucidated.

E2F1 ProteinQ01094 (Uniprot-TrEMBL)
E2F2 ProteinQ14209 (Uniprot-TrEMBL)
E2F3 ProteinO00716 (Uniprot-TrEMBL)
EED Gene:E2F1/2/3:DP1/2ComplexR-HSA-3240767 (Reactome)
EED Gene ProteinENSG00000074266 (Ensembl)
EED GeneGeneProductENSG00000074266 (Ensembl)
EED ProteinO75530 (Uniprot-TrEMBL)
EEDProteinO75530 (Uniprot-TrEMBL)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
EZH2 Gene:E2F1/2/3:DP1/2ComplexR-HSA-3240771 (Reactome)
EZH2 Gene ProteinENSG00000106462 (Ensembl)
EZH2 GeneGeneProductENSG00000106462 (Ensembl)
EZH2 ProteinQ15910 (Uniprot-TrEMBL)
EZH2ProteinQ15910 (Uniprot-TrEMBL)
FOSProteinP01100 (Uniprot-TrEMBL)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFJ ProteinQ9BTM1 (Uniprot-TrEMBL)
H2AFV ProteinQ71UI9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
IFNB1ProteinP01574 (Uniprot-TrEMBL)
INK4ComplexR-HSA-182588 (Reactome)
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.

JUNProteinP05412 (Uniprot-TrEMBL)
KDM6B Gene ProteinENSG00000132510 (Ensembl)
KDM6B GeneGeneProductENSG00000132510 (Ensembl)
KDM6B ProteinO15054 (Uniprot-TrEMBL)
KDM6B:Fe2+ComplexR-HSA-3222589 (Reactome)
KDM6BProteinO15054 (Uniprot-TrEMBL)
MAP2K3 ProteinP46734 (Uniprot-TrEMBL)
MAP2K4ProteinP45985 (Uniprot-TrEMBL)
MAP2K6 ProteinP52564 (Uniprot-TrEMBL)
MAP3K5 ProteinQ99683 (Uniprot-TrEMBL)
MAP3K5:TXNComplexR-HSA-3225859 (Reactome)
MAP3K5ProteinQ99683 (Uniprot-TrEMBL)
MAP4K4 ProteinO95819 (Uniprot-TrEMBL)
MAP4K4 gene ProteinENSG00000071054 (Ensembl)
MAPK10 ProteinP53779 (Uniprot-TrEMBL)
MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
MAPK8 ProteinP45983 (Uniprot-TrEMBL)
MAPK8/9/10ComplexR-HSA-450289 (Reactome)
MAPK9 ProteinP45984 (Uniprot-TrEMBL)
MAPKAPK2 ProteinP49137 (Uniprot-TrEMBL)
MAPKAPK3 ProteinQ16644 (Uniprot-TrEMBL)
MAPKAPK5 ProteinQ8IW41 (Uniprot-TrEMBL)
MDM4 ProteinO15151 (Uniprot-TrEMBL)
MINK1 ProteinQ8N4C8 (Uniprot-TrEMBL)
MINK1 gene ProteinENSG00000141503 (Ensembl)
MINK1/TNIK genesComplexR-HSA-8979184 (Reactome)
MINK1/TNIKComplexR-HSA-3214892 (Reactome)
MKK3/MKK6ComplexR-HSA-167916 (Reactome)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
Me3K-28-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Me3K-28-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
Me3K-28-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome)
Oncogene Induced SenescencePathwayR-HSA-2559585 (Reactome) Oncogene-induced senescence is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.

Oncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16-INK4A and p14-ARF. p16-INK4A and p14-ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16-INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16-INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15-INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15-INK4B, together with p16-INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15-INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15-INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).

MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16-INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16-INK4A transcription (Ohtani et al. 2004).

Transcription of p14-ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14-ARF promoter (Parisi et al. 2002).

Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.

Oncogenic MAPK signalingPathwayR-HSA-6802957 (Reactome) The importance of the RAS/RAF/MAPK cascade in regulating cellular proliferation, differentiation and survival is highlighted by the fact that components of the pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF. RAS pathway activation is also achieved in a smaller subset of cancers by loss-of-function mutations in negative regulators of RAS signaling, such as the RAS GAP NF1(reviewed in Prior et al, 2012; Pylayeva-Gupta et al, 2011; Stephen et al, 2014; Lavoie and Therrien, 2015; Lito et al, 2013; Samatar and Poulikakos, 2014; Maertens and Cichowski, 2014).
PHC1 ProteinP78364 (Uniprot-TrEMBL)
PHC2 ProteinQ8IXK0 (Uniprot-TrEMBL)
PHC3 ProteinQ8NDX5 (Uniprot-TrEMBL)
PRC1.4ComplexR-HSA-3229073 (Reactome)
PRC2 (EZH2) CoreComplexR-HSA-212285 (Reactome) The human Polycomb Repressive Complex 2 (PRC2) is homologous to the Drosophila PRC2. The core PRC2 contains EZH2, a histone methyltransferase specific for lysine 27 and lysine 9 of histone H3. The methyltransferase activity of EZH2 is dependent on its association with PRC2. The complex contains other uncharacterized proteins, its composition may vary in different tissues and developmental stages, and the order of assembly of the complex is presently unknown.
PolyUb-TP53 ProteinP04637 (Uniprot-TrEMBL)
PolyUb-TP53 TetramerComplexR-HSA-3209186 (Reactome)
RBBP4 ProteinQ09028 (Uniprot-TrEMBL)
RBBP4ProteinQ09028 (Uniprot-TrEMBL)
RBBP7 ProteinQ16576 (Uniprot-TrEMBL)
RBBP7ProteinQ16576 (Uniprot-TrEMBL)
RING1 ProteinQ06587 (Uniprot-TrEMBL)
RNF2 ProteinQ99496 (Uniprot-TrEMBL)
ROSMetaboliteCHEBI:26523 (ChEBI)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SCMH1-2 ProteinQ96GD3-2 (Uniprot-TrEMBL)
SUCCAMetaboliteCHEBI:15741 (ChEBI)
SUZ12 Gene:E2F1/2/3:DP1/2ComplexR-HSA-3240769 (Reactome)
SUZ12 Gene ProteinENSG00000178691 (Ensembl)
SUZ12 GeneGeneProductENSG00000178691 (Ensembl)
SUZ12 ProteinQ15022 (Uniprot-TrEMBL)
SUZ12ProteinQ15022 (Uniprot-TrEMBL)
Senescence-Associated Secretory Phenotype (SASP)PathwayR-HSA-2559582 (Reactome) The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013).

Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.

IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).

Please refer to Young and Narita 2009 for a recent review.

TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TFDP1,TFDP2:E2F1,E2F2,E2F3ComplexR-HSA-1227905 (Reactome)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TNIK ProteinQ9UKE5 (Uniprot-TrEMBL)
TNIK gene ProteinENSG00000154310 (Ensembl)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
TXN ProteinP10599 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-68524 (Reactome)
miR-24

Nonendonucleolytic

RISC
ComplexR-HSA-3209134 (Reactome) The RNA-induced silencing complex contains an Argonaute (AGO) protein, whose PAZ domain binds the 3' end of the miRNA. The PIWI domain of AGO is responsible for cleavage of target RNAs, that is, RNAs complementary to the miRNA. Only AGO2 (EIF2C2) is capable of cleavage, however. AGO1 (EIF2C1), AGO3 (EIF2C3), and AGO4 (EIF2C4) repress translation of target RNAs by binding without cleavage. In vivo, cleavage by AGO2 and repression of translation by all AGOs require interaction with a TNRC6 protein (GW182 protein) and MOV10. The interaction with TNRC6 proteins is also responsible for localizing the AGO complex to Processing Bodies (P-bodies). Tethering of the C-terminal domain of a TNRC6 protein to a mRNA is sufficient to cause repression of translation.
miR-24-1 ProteinMI0000080 (miRBase mature sequence)
miR-24-2 ProteinMI0000081 (miRBase mature sequence)
p-2S-cJUN:p-2S,2T-cFOS:KDM6B GeneComplexR-HSA-3222535 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSComplexR-HSA-450327 (Reactome)
p-MAP2K4/p-MAP2K7ComplexR-HSA-450299 (Reactome)
p-MAPK8/9/10ComplexR-HSA-450226 (Reactome)
p-MAPK8/9/10ComplexR-HSA-450253 (Reactome)
p-MKK3/p-MKK6ComplexR-HSA-167984 (Reactome)
p-MKK3/p-MKK6ComplexR-HSA-450343 (Reactome)
p-PRC1.4 complexComplexR-HSA-3229114 (Reactome)
p-S,2T-MAPKAPK3 ProteinQ16644 (Uniprot-TrEMBL)
p-S-BMI1 ProteinP35226 (Uniprot-TrEMBL)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
ComplexR-HSA-6804885 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
ComplexR-HSA-6804745 (Reactome)
p-S166,S188-MDM2 ProteinQ00987 (Uniprot-TrEMBL)
p-S189,T193-MAP2K3 ProteinP46734 (Uniprot-TrEMBL)
p-S207,T211-MAP2K6 ProteinP52564 (Uniprot-TrEMBL)
p-S257,T261-MAP2K4 ProteinP45985 (Uniprot-TrEMBL)
p-S257,T261-MAP2K4ProteinP45985 (Uniprot-TrEMBL)
p-S271,T275-MAP2K7 ProteinO14733 (Uniprot-TrEMBL)
p-S37-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S37-TP53 TetramerComplexR-HSA-3239015 (Reactome)
p-S63,S73-JUN ProteinP05412 (Uniprot-TrEMBL)
p-S63,S73-JUNProteinP05412 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-198701 (Reactome)
p-T,Y-MAPK8 ProteinP45983 (Uniprot-TrEMBL)
p-T180,Y182-MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
p-T182-MAPKAPK5 ProteinQ8IW41 (Uniprot-TrEMBL)
p-T183,Y185-MAPK9 ProteinP45984 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T221,Y223-MAPK10 ProteinP53779 (Uniprot-TrEMBL)
p-T222,S272,T334-MAPKAPK2 ProteinP49137 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOS ProteinP01100 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOSProteinP01100 (Uniprot-TrEMBL)
p-p38 MAPK:p-MAPKAPK2/3ComplexR-HSA-450254 (Reactome)
p14-ARF ProteinQ8N726 (Uniprot-TrEMBL)
p14-ARF mRNA ProteinENST00000579755 (Ensembl)
p14-ARF mRNARnaENST00000579755 (Ensembl)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53ComplexR-HSA-6804999 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4ComplexR-HSA-6804995 (Reactome)
p14-ARFProteinQ8N726 (Uniprot-TrEMBL)
p16-INK4A mRNA ProteinENST00000304494 (Ensembl)
p16-INK4A mRNARnaENST00000304494 (Ensembl)
p16-INK4a ProteinP42771 (Uniprot-TrEMBL)
p16-INK4a/p14-ARF

mRNA: miR-24 Nonendonucleolytic

RISC
ComplexR-HSA-3209131 (Reactome)
p16-INK4a/p14-ARF mRNAComplexR-HSA-3209130 (Reactome)
p16-INK4aProteinP42771 (Uniprot-TrEMBL)
p38 MAPK:MAPKAPK2/3ComplexR-HSA-450269 (Reactome)
p38 MAPK:MAPKAPK5ComplexR-HSA-3239002 (Reactome)
phospho-MAPK p38:p-MAPKAPK3ComplexR-HSA-3772127 (Reactome)
phospho-p38 MAPK:p-T-182-MAPKAPK5ComplexR-HSA-3239017 (Reactome)
phospho-p38 MAPK: MAPKAPK2/3ComplexR-HSA-450213 (Reactome)
phospho-p38 MAPK: MAPKAPK5ComplexR-HSA-3239009 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2OGR-HSA-3222593 (Reactome)
2xHC-TXNArrowR-HSA-3225851 (Reactome)
ADPArrowR-HSA-168136 (Reactome)
ADPArrowR-HSA-168162 (Reactome)
ADPArrowR-HSA-3228469 (Reactome)
ADPArrowR-HSA-3229102 (Reactome)
ADPArrowR-HSA-3229152 (Reactome)
ADPArrowR-HSA-3238999 (Reactome)
ADPArrowR-HSA-3239014 (Reactome)
ADPArrowR-HSA-3239019 (Reactome)
ADPArrowR-HSA-450222 (Reactome)
ADPArrowR-HSA-450325 (Reactome)
ADPArrowR-HSA-450333 (Reactome)
ATPR-HSA-168136 (Reactome)
ATPR-HSA-168162 (Reactome)
ATPR-HSA-3228469 (Reactome)
ATPR-HSA-3229102 (Reactome)
ATPR-HSA-3229152 (Reactome)
ATPR-HSA-3238999 (Reactome)
ATPR-HSA-3239014 (Reactome)
ATPR-HSA-3239019 (Reactome)
ATPR-HSA-450222 (Reactome)
ATPR-HSA-450325 (Reactome)
ATPR-HSA-450333 (Reactome)
AdoHcyArrowR-HSA-3240295 (Reactome)
AdoMetR-HSA-3240295 (Reactome)
CDK4,CDK6:INK4ArrowR-HSA-182594 (Reactome)
CDK4,CDK6R-HSA-182594 (Reactome)
CDKN2A Gene:H3K27Me3-Nucleosome:PRC1.4ArrowR-HSA-3229089 (Reactome)
CDKN2A Gene:H3K27Me3-Nucleosome:PRC1.4R-HSA-3229102 (Reactome)
CDKN2A Gene:H3K27Me3-Nucleosome:PRC1.4TBarR-HSA-3223200 (Reactome)
CDKN2A Gene:H3K27Me3-NucleosomeArrowR-HSA-3229102 (Reactome)
CDKN2A Gene:H3K27Me3-NucleosomeArrowR-HSA-3240295 (Reactome)
CDKN2A Gene:H3K27Me3-NucleosomeR-HSA-3222593 (Reactome)
CDKN2A Gene:H3K27Me3-NucleosomeR-HSA-3229089 (Reactome)
CDKN2A Gene:NucleosomeArrowR-HSA-3222593 (Reactome)
CDKN2A Gene:NucleosomeR-HSA-3240295 (Reactome)
CDKN2A geneR-HSA-3223200 (Reactome)
CDKN2A geneR-HSA-3229138 (Reactome)
EED Gene:E2F1/2/3:DP1/2ArrowR-HSA-3240765 (Reactome)
EED Gene:E2F1/2/3:DP1/2ArrowR-HSA-3240782 (Reactome)
EED GeneR-HSA-3240765 (Reactome)
EED GeneR-HSA-3240782 (Reactome)
EEDArrowR-HSA-3240782 (Reactome)
EEDR-HSA-3240957 (Reactome)
EZH2 Gene:E2F1/2/3:DP1/2ArrowR-HSA-3240777 (Reactome)
EZH2 Gene:E2F1/2/3:DP1/2ArrowR-HSA-3240783 (Reactome)
EZH2 GeneR-HSA-3240777 (Reactome)
EZH2 GeneR-HSA-3240783 (Reactome)
EZH2ArrowR-HSA-3240783 (Reactome)
EZH2R-HSA-3240957 (Reactome)
FOSR-HSA-450325 (Reactome)
Fe2+R-HSA-8979071 (Reactome)
IFNB1ArrowR-HSA-3223236 (Reactome)
INK4R-HSA-182594 (Reactome)
JUNR-HSA-168136 (Reactome)
KDM6B GeneR-HSA-3222533 (Reactome)
KDM6B GeneR-HSA-3222546 (Reactome)
KDM6B:Fe2+ArrowR-HSA-3223200 (Reactome)
KDM6B:Fe2+ArrowR-HSA-8979071 (Reactome)
KDM6B:Fe2+mim-catalysisR-HSA-3222593 (Reactome)
KDM6BArrowR-HSA-3222546 (Reactome)
KDM6BR-HSA-8979071 (Reactome)
MAP2K4R-HSA-3229152 (Reactome)
MAP3K5:TXNR-HSA-3225851 (Reactome)
MAP3K5ArrowR-HSA-3225851 (Reactome)
MAP3K5mim-catalysisR-HSA-3228469 (Reactome)
MAP3K5mim-catalysisR-HSA-3229152 (Reactome)
MAPK8/9/10R-HSA-168162 (Reactome)
MINK1/TNIK genesR-HSA-3225867 (Reactome)
MINK1/TNIKArrowR-HSA-3225851 (Reactome)
MINK1/TNIKArrowR-HSA-3225867 (Reactome)
MKK3/MKK6R-HSA-3228469 (Reactome)
PRC1.4R-HSA-3229089 (Reactome)
PRC2 (EZH2) CoreArrowR-HSA-3240957 (Reactome)
PRC2 (EZH2) Coremim-catalysisR-HSA-3240295 (Reactome)
PolyUb-TP53 TetramerArrowR-HSA-6804879 (Reactome)
R-HSA-168136 (Reactome) JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus.
R-HSA-168162 (Reactome) Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK.

JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183).

R-HSA-182594 (Reactome) Prior to mitogen activation, the inhibitory proteins of the INK4 family (p15, p16, p18, and p19) associate with the catalytic domains of free CDK4 and CDK6, preventing their association with D type cyclins (CCND1, CCND2 and CCND3), and thus their activation (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995). Inactivation and defects of RB1 strongly upregulate p16-INK4A (Parry et al. 1995).
R-HSA-3209111 (Reactome) MicroRNA miR-24 inhibits translation of p14-ARF mRNA without causing mRNA degradation. This results in high p14-ARF transcript level accompanied by low p14-ARF protein level (To et al. 2012).
R-HSA-3209114 (Reactome) MicroRNA miR-24 inhibits translation of p16-INK4A mRNA without causing mRNA degradation. This results in high p16-INK4A transcript level accompanied by low p16-INK4A protein level (Lal et al. 2008).
R-HSA-3209151 (Reactome) MicroRNA miR-24 is able to bind both p16-INK4A mRNA (Lal et al. 2008) and p14-ARF mRNA (To et al. 2012) through their shared 3'UTR. miR-24 inhibits translation of p16-INK4A and p14-ARF mRNAs, but does not induce mRNA degradation, resulting in expression of high levels of p16-INK4A and p14-ARF transcripts, while protein levels of p16-INK4A and p14-ARF are low (Lal et al. 2008, To et al. 2012).
R-HSA-3222533 (Reactome) Binding of the AP-1 (JUN:FOS) subunit JUN to the KDM6B (JMJD3) promoter, as well as the transcription of KDM6B gene increases after ERK activation (Lin et al. 2012).
R-HSA-3222546 (Reactome) Binding of the AP-1 (JUN:FOS) subunit JUN to the KDM6B (JMJD3) promoter, as well as the transcription of KDM6B gene increases after ERK activation (Lin et al. 2012).
R-HSA-3222593 (Reactome) Histone demethylase KDM6B (JMJD3) demethylates H3K27Me3 marks i.e. removes methyl groups from lysine 28 of histone HIST1H3A on CDKN2A locus, thereby activating CDKN2A transcription. In human cells, H3K27Me3 marks are predominantly found around the first exon of p16-INK4A, and KDM6B therefore activates p16-INK4A transcription but not p14-ARF transcription. In mouse cells, H3K27Me3 marks are found throughout the Cdkn2a locus and Kdm6b demethylase activity induces transcription of both p16-Ink4a and p19-Arf. KDM6B action promotes both the oncogene-induced and oxidative stress-induced senescence (Agger et al. 2009, Barradas et al. 2009).
R-HSA-3223200 (Reactome) While binding of the PRC1.4 complex to the H3K27Me3 mark on the promoter of p16-INK4A inhibits p16-INK4A transcription (Dietrich et al. 2007, Agherbi et al. 2009), KDM6B-mediated demethylation of lysine 28 of histone HIST1H3A (the removal of H3K27Me3 mark) stimulates p16-INK4A transcription (Agger et al. 2009, Barradas et al. 2009).
R-HSA-3223236 (Reactome) Oncogenic RAS signaling leads to mitochondrial dysfunction, resulting in increased mitochondrial production of reactive oxygen species (ROS), which contributes to cellular senescence (Moiseeva et al. 2009). The exact biochemical mechanism of RAS-induced mitochondrial dysfunction has not been established. Prolonged exposure to interferon-beta (INFB, INF-beta) also results in increased ROS concentration in the cell and triggers cellular senescence (Moiseeva et al. 2006). Although the positive regulation of ROS production by interferon signaling is well documented (Huang et al. 2007, Yang et al. 2007, Yim et al. 2012), the precise mechanism is not known.
R-HSA-3225851 (Reactome) When in reduced form, TXN (thioredoxin) binds the amino terminus of MAP3K5 (ASK1) and inhibits its kinase activity. Once reactive oxygen species (ROS) oxidize TXN, TXN dissociates from MAP3K5, enabling MAP3K5 to phosphorylate downstream targets (Saitoh et al. 1998). Increased expression and activity of MINK1 (MINK) (and possibly other Ste20 family kinases TNIK and MAP4K), which is induced by ROS generated as a consequence of oncogenic RAS signaling, may contribute to MAP3K5 activation (Nicke et al. 2005).
R-HSA-3225867 (Reactome) Reactive oxygen species (ROS) generated as a consequence of oncogenic RAS signaling induce expression and activation of Ste20 family kinases MINK1 (MINK), TNIK and, possibly, MAP4K4, which contributes to growth arrest and cellular senescence (Nicke et al. 2005).
R-HSA-3228469 (Reactome) MAP3K5 (ASK1) phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997). A conserved docking site, DVD, at the C-terminus of MAP2K3 and MAP2K6 is needed for the interaction with MAP3K5 and MAP3K5-mediated activation (Takekawa et al. 2005).
R-HSA-3229089 (Reactome) PRC1.4 complex, which includes PCGF4 (BMI1), RING1 (RING1A) and RNF2 (RING1B) ubiquitin ligases and CBX proteins (Gao et al. 2012), binds nucleosomes trimethylated on the lysine residue 28 of histone H3 (Me3K-28-HIST1H3A, also known as H3K27Me3), located on CDKN2A promoter (Dietrich et al. 2007, Agherbi et al. 2009, Voncken et al. 2005), through interaction of BMI1 and CBX proteins with Me3K-28-HIST1H3A mark (Gao et al. 2012, Dietrich et al. 2007).
R-HSA-3229102 (Reactome) In response to stress-activated p38 signaling, MAPKAPK3 phosphorylates BMI1, leading to the dissociation of the PRC1.4 complex from chromatin and transcription of p14-ARF (Voncken et al. 2005).
R-HSA-3229138 (Reactome) Transcription of p14-ARF in response to oxidative stress induced p38 signaling is positively regulated by MAPKAPK3-mediated phosphorylation of BMI1 and the subsequent dissociation of the PRC1.4 complex from the CDKN2A locus (Voncken et al. 2005).
R-HSA-3229152 (Reactome) MAP3K5 (ASK1) phosphorylates and activates MAP2K4 (SEK1) (Ichijo et al. 1997). MAP3K5-mediated phosphorylation of MAP2K4 may be facilitated by MAPK8IP3 (JSAP1) (Matsuura et al. 2002).
R-HSA-3238999 (Reactome) MAPKAPK5 (PRAK) forms a complex with MAPK14 (p38 alpha) or MAPK11 (p38 beta) irrespective of the phosphorylation status and kinase activity of MAPKAPK5, MAPK14 and MAPK11 (New et al. 2003). Phosphorylation of p38 alpha and p38 beta by MKK3 or MKK6 (Raingeaud et al. 1996), however, is required for the subsequent activation of MAPKAPK5 by p38 MAPK (New et al. 1998, Sun et al. 2007).
R-HSA-3239014 (Reactome) Activated MAPKAPK5 (PRAK) phosphorylates TP53 (p53) on serine residue S37, thereby activating it. MAPKAPK5-mediated phosphorylation of TP53 promotes growth arrest and senescence induced by oncogenic RAS, but is not needed for TP53-dependent growth arrest in response to DNA damage (Sun et al. 2007).
R-HSA-3239019 (Reactome) MAPK14 (p38 alpha) and MAPK11 (p38 beta) phosphorylate MAPKAPK5 (PRAK) on threonine residue 182, located in the conserved LMTP site in the T-loop of the kinase domain. Phosphorylation of T182 is necessary for the MAPKAPK5 catalytic activity (New et al. 1998).
R-HSA-3240295 (Reactome) The Polycomb repressor complex 2 (PRC2) trimethylates histone HIST1H3A (H3) on lysine residue 28, producing an H3K27Me3 mark along the CDKN2A locus. The H3K27Me3 subsequently serves as a docking site for the PRC1.4 complex that includes BMI1 and CBX8 or CBX7 and acts to repress p16-INK4A and, probably p14-ARF transcription (Bracken et al. 2007). Proteins of the RB family may be involved in the regulation of enzymatic activity or the recruitment of PRC2 to the CDKN2A locus (Kotake et al. 2007). Conflicting results exist on the regulation of p14-ARF expression by Polycomb group (PcG) proteins involved in the formation of PRC2 and PRC1. While p14-ARF does not seem to be regulated by PcGs in human fibroblasts, in contrast to mouse embryonic fibroblasts - MEFs (Bracken et al. 2007), experiments on human CD34+ bone marrow cells (Bracken et al. 2007) and U2OS osteosarcoma cell line (Voncken et al. 2005) implicate PcGs in the regulation of p14-ARF transcription.
R-HSA-3240765 (Reactome) EED gene contains several E2F binding sites in its promoter, and these E2F-binding sites are needed for the responsiveness of EED promoter to E2F1, E2F2 and E2F3. Only E2F1 with intact DNA-binding domain stimulates EED transcription. Binding of E2F3 to EED promoter was directly demonstrated by ChIP (Bracken et al. 2003).
R-HSA-3240766 (Reactome) E2F1, E2F2, E2F3 and E2F4 are all able to bind the promoter of SUZ12 (ChET 9) (Weinmann et al 2001), a subunit of the Polycomb repressor complex 2 (PRC2).
R-HSA-3240777 (Reactome) EZH2 gene contains several E2F binding sites in its promoter, and these E2F-binding sites are needed for the responsiveness of EZH2 promoter to E2F1, E2F2 and E2F3. Only E2F1 with intact DNA-binding domain stimulates EZH2 transcription. Binding of E2F3 to EZH2 promoter was directly demonstrated by ChIP (Bracken et al. 2003).
R-HSA-3240782 (Reactome) In growing cells, the transcription of EED gene, which codes for a subunit of the Polycomb repressor complex 2 (PRC2), is stimulated by E2F1, E2F2 and E2F3 that bind E2F sites in the EED promoter. Direct binding to EED promoter was directly experimentally examined and confirmed only for E2F3, while it was also demonstrated that E2F1-mediated stimulation of EED gene transcription depends on the intact DNA-binding domain of E2F1. E2F4 also binds EED promoter directly, with the strongest enrichment in G0 (Bracken et al. 2003).
R-HSA-3240783 (Reactome) In growing cells, the transcription of EZH2 methyltransferase gene, which codes for a subunit of the Polycomb repressor complex 2 (PRC2), is stimulated by E2F1, E2F2 and E2F3 that bind E2F sites in the EZH2 promoter. Direct binding to EZH2 promoter was directly experimentally examined and confirmed only for E2F3, while it was also demonstrated that E2F1-mediated stimulation of EZH2 gene transcription depends on the intact DNA-binding domain of E2F1. E2F4 also binds EZH2 promoter directly, with the strongest enrichment in G0, which is likely needed for repression of EZH2 transcription in non-growing cells (Bracken et al. 2003).
R-HSA-3240787 (Reactome) E2F1 was directly shown to activate the transcription from the SUZ12 promoter, and it is assumed that E2F2 and E2F3, which also bind SUZ12 promoter, are able to activate SUZ12 transcription (Weinmann et al. 2001).
R-HSA-3240957 (Reactome) The Polycomb repressor complex 2, PRC2-EZH2, consists of 5 proteins: EZH2, EED, RBBP4 (RBAP48), RBBP7 (RBAP46) and SUZ12, and is evolutionarily conserved. While RBBP4 and RBBP7 are proteins involved in various chromatin remodeling complexes, EZH2, EED and SUZ12 belong to the Polycomb group. EZH2 is also a member of the SET family of histone methyltransferases, and PRC2 trimethylates lysine residues K10 and K28 of HIST1H3A (histone H3), with K28 being the preferred site (Kuzmichev et al. 2002).
R-HSA-450222 (Reactome) Human p38 MAPK alpha forms a complex with MK2 even when the signaling pathway is not activated. This heterodimer is found mainly in the nucleus. The crystal structure of the unphosphorylated p38alpha-MK2 heterodimer was determined. The C-terminal regulatory domain of MK2 binds in the docking groove of p38 MAPK alpha, and the ATP-binding sites of both kinases are at the heterodimer interface (ter Haar et al. 2007).

Upon activation, p38 MAPK alpha activates MK2 by phosphorylating Thr-222, Ser-272, and Thr-334 (Ben-Levy et al. 1995).

The phosphorylation of MK2 at Thr-334 attenuates the affinity of the binary complex MK2:p38 alpha by an order of magnitude and leads to a large conformational change of an autoinhibitory domain in MK2. This conformational change unmasks not only the MK2 substrate-binding site but also the MK2 nuclear export signal (NES) thus leading to the MK2:p38 alpha translocation from the nucleus to the cytoplasm. Cytoplasmic active MK2 then phosphorylates downstream targets such as the heat-shock protein HSP27 and tristetraprolin (TTP) (Meng et al. 2002, Lukas et al. 2004, White et al. 2007).

MAPKAPK (MAPK-activated protein) kinase 3 (MK3, also known as 3pK) has been identified as the second p38 MAPK-activated kinase that is stimulated by different stresses (McLaughlin et al. 1996; Sithanandam et al. 1996; reviewed in Gaestel 2006). MK3 shows 75% sequence identity to MK2 and, like MK2, is activated by p38 MAPK alpha and p38 MAPK beta. MK3 phosphorylates peptide substrates with kinetic constants similar to MK2 and phosphorylates the same serine residues in HSP27 at the same relative rates as MK2 (Clifton et al. 1996) indicating an identical phosphorylation-site consensus sequence. Hence, it is assumed that its substrate spectrum is either identical to or at least overlapping with MK2.

R-HSA-450292 (Reactome) The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995).
R-HSA-450296 (Reactome) The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus.
R-HSA-450325 (Reactome) The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity.

On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.

Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover.

R-HSA-450333 (Reactome) The MAPK level components of this cascade are p38MAPK-alpha, -beta, -gamma and -sigma. All of those isoforms are activated by phosphorylation of the Thr and Tyr in the Thr-Gly-Tyr motif in their activation loops.
R-HSA-450348 (Reactome) c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors.
R-HSA-6804879 (Reactome) MDM2 is an ubiquitin ligase whose expression is positively regulated by TP53 (p53) (Wu et al. 1993). MDM2 binds TP53 tetramer (Maki 1999) and promotes its ubiquitination and subsequent degradation (Fuchs et al. 1998). Formation of MDM2 homodimers (Cheng et al. 2011) or heterodimers with MDM4 (MDMX) is needed for efficient ubiquitination of TP53 (Linares et al. 2003). While MDM2-TP53 binding occurs at the amino-terminus of TP53, MDM2 ubiquitinates TP53 lysine residues at the carboxy-terminus. Acetylation of those lysines can inhibit MDM2-dependent ubiquitination (Li et al. 2002).
R-HSA-6804996 (Reactome) Binding of p14-ARF to MDM2 decreases the half-life of MDM2, likely through promoting MDM2 degradation. Thus, p14-ARF inhibits MDM2-mediated ubiquitination and degradation of TP53 (Zhang et al. 1998).
R-HSA-6804998 (Reactome) p14-ARF forms a complex with TP53-bound MDM2 by interacting with the C-terminus of MDM2, while the N-terminus of MDM2 is involved in TP53 (p53) binding. p14-ARF cannot associate with TP53 in the absence of MDM2 (Zhang et al. 1998).
R-HSA-8979071 (Reactome) KDM6B (JMJD3) binds iron. Formation of complex with Fe(II) is needed for the catalytic activity of KDM6B (De Santa et al. 2007).
RBBP4R-HSA-3240957 (Reactome)
RBBP7R-HSA-3240957 (Reactome)
ROSArrowR-HSA-3223236 (Reactome)
ROSArrowR-HSA-3225867 (Reactome)
ROSR-HSA-3225851 (Reactome)
SUCCAArrowR-HSA-3222593 (Reactome)
SUZ12 Gene:E2F1/2/3:DP1/2ArrowR-HSA-3240766 (Reactome)
SUZ12 Gene:E2F1/2/3:DP1/2ArrowR-HSA-3240787 (Reactome)
SUZ12 GeneR-HSA-3240766 (Reactome)
SUZ12 GeneR-HSA-3240787 (Reactome)
SUZ12ArrowR-HSA-3240787 (Reactome)
SUZ12R-HSA-3240957 (Reactome)
TFDP1,TFDP2:E2F1,E2F2,E2F3R-HSA-3240765 (Reactome)
TFDP1,TFDP2:E2F1,E2F2,E2F3R-HSA-3240766 (Reactome)
TFDP1,TFDP2:E2F1,E2F2,E2F3R-HSA-3240777 (Reactome)
TP53 TetramerArrowR-HSA-6804996 (Reactome)
TP53 TetramerR-HSA-3239014 (Reactome)
UbR-HSA-6804879 (Reactome)
miR-24

Nonendonucleolytic

RISC
R-HSA-3209151 (Reactome)
p-2S-cJUN:p-2S,2T-cFOS:KDM6B GeneArrowR-HSA-3222533 (Reactome)
p-2S-cJUN:p-2S,2T-cFOS:KDM6B GeneArrowR-HSA-3222546 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSArrowR-HSA-450292 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSR-HSA-3222533 (Reactome)
p-MAP2K4/p-MAP2K7mim-catalysisR-HSA-168162 (Reactome)
p-MAPK8/9/10ArrowR-HSA-168162 (Reactome)
p-MAPK8/9/10ArrowR-HSA-450348 (Reactome)
p-MAPK8/9/10R-HSA-450348 (Reactome)
p-MAPK8/9/10mim-catalysisR-HSA-168136 (Reactome)
p-MKK3/p-MKK6ArrowR-HSA-3228469 (Reactome)
p-MKK3/p-MKK6ArrowR-HSA-450296 (Reactome)
p-MKK3/p-MKK6R-HSA-450296 (Reactome)
p-MKK3/p-MKK6mim-catalysisR-HSA-3238999 (Reactome)
p-MKK3/p-MKK6mim-catalysisR-HSA-450333 (Reactome)
p-PRC1.4 complexArrowR-HSA-3229102 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
R-HSA-6804879 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
R-HSA-6804998 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2,MDM4:TP53
mim-catalysisR-HSA-6804879 (Reactome)
p-S166,S188-MDM2

dimer,

p-S166,S188-MDM2:MDM4
ArrowR-HSA-6804879 (Reactome)
p-S257,T261-MAP2K4ArrowR-HSA-3229152 (Reactome)
p-S37-TP53 TetramerArrowR-HSA-3239014 (Reactome)
p-S63,S73-JUNArrowR-HSA-168136 (Reactome)
p-S63,S73-JUNR-HSA-450292 (Reactome)
p-T,Y MAPK dimersArrowR-HSA-3223236 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-450325 (Reactome)
p-T325,T331,S362,S374-FOSArrowR-HSA-450325 (Reactome)
p-T325,T331,S362,S374-FOSR-HSA-450292 (Reactome)
p-p38 MAPK:p-MAPKAPK2/3ArrowR-HSA-450222 (Reactome)
p14-ARF mRNAArrowR-HSA-3229138 (Reactome)
p14-ARF mRNAR-HSA-3209111 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53ArrowR-HSA-6804998 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53R-HSA-6804996 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4ArrowR-HSA-6804996 (Reactome)
p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4TBarR-HSA-6804879 (Reactome)
p14-ARFArrowR-HSA-3209111 (Reactome)
p14-ARFR-HSA-6804998 (Reactome)
p16-INK4A mRNAArrowR-HSA-3223200 (Reactome)
p16-INK4A mRNAR-HSA-3209114 (Reactome)
p16-INK4a/p14-ARF

mRNA: miR-24 Nonendonucleolytic

RISC
ArrowR-HSA-3209151 (Reactome)
p16-INK4a/p14-ARF

mRNA: miR-24 Nonendonucleolytic

RISC
TBarR-HSA-3209111 (Reactome)
p16-INK4a/p14-ARF

mRNA: miR-24 Nonendonucleolytic

RISC
TBarR-HSA-3209114 (Reactome)
p16-INK4a/p14-ARF mRNAR-HSA-3209151 (Reactome)
p16-INK4aArrowR-HSA-3209114 (Reactome)
p38 MAPK:MAPKAPK2/3R-HSA-450333 (Reactome)
p38 MAPK:MAPKAPK5R-HSA-3238999 (Reactome)
phospho-MAPK p38:p-MAPKAPK3ArrowR-HSA-3229138 (Reactome)
phospho-MAPK p38:p-MAPKAPK3mim-catalysisR-HSA-3229102 (Reactome)
phospho-p38 MAPK:p-T-182-MAPKAPK5ArrowR-HSA-3239019 (Reactome)
phospho-p38 MAPK:p-T-182-MAPKAPK5mim-catalysisR-HSA-3239014 (Reactome)
phospho-p38 MAPK: MAPKAPK2/3ArrowR-HSA-450333 (Reactome)
phospho-p38 MAPK: MAPKAPK2/3R-HSA-450222 (Reactome)
phospho-p38 MAPK: MAPKAPK2/3mim-catalysisR-HSA-450222 (Reactome)
phospho-p38 MAPK: MAPKAPK5ArrowR-HSA-3238999 (Reactome)
phospho-p38 MAPK: MAPKAPK5R-HSA-3239019 (Reactome)
phospho-p38 MAPK: MAPKAPK5mim-catalysisR-HSA-3239019 (Reactome)

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