Oxidative Stress Induced Senescence (Homo sapiens)

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1, 4, 10, 15, 18...66, 80110, 144115279, 62, 12215, 99, 126, 13311511, 24, 31, 47, 54...872015, 9910, 191, 23, 26, 40, 49...7786, 111, 116, 14858, 1383517, 22, 64, 127, 14770873, 5, 76, 97, 13259, 87, 126, 13329, 8135, 10913818116182711315, 20, 7733, 14939, 1441834, 60, 13086, 1071481091885, 107nucleoplasmmitochondrial matrixcytosolHIST1H2BJ TP53 CDK4 EEDGene:E2F1/2/3:DP1/2HIST2H2AA3 ATPmiR-24-2 p14ARF p16INK4A mRNAHIST1H2BL HIST1H2BD INK4E2F1 p-S166,S188-MDM2 p14ARFSUZ12 CDK6 p-T180,Y182-MAPK11 p16INK4A UbEIF2C4 SCMH1-2 HIST1H2BB p-S63,S73-JUN phospho-p38MAPK:p-T-182-MAPKAPK5CBX4 RBBP4HIST1H2BK HIST1H4 E2F1 MAP3K5 TNIK MAPK8,9,10CBX8 UBC(609-684) HIST1H2AD H2AFZ ATPHIST1H2BD PHC1 CBX2 p-T183,Y185-MAPK9 ADPUBC(229-304) HIST2H2BE CBX8 p-T202,Y204-MAPK3 CDKN2C HIST1H2BK SUZ12 Gene p-S257,T261-MAP2K4RING1 HIST1H4 ADPEIF2C1 MAP3K5TNIK gene EZH2 GeneMe3K-28-HIST1H3A p-T222,S272,T334-MAPKAPK2 p-S189,T193-MAP2K3,p-S207,T211-MAP2K6TP53 Me3K-28-HIST2H3A HIST1H2BD p14ARF mRNACDK4,CDK6:INK4HIST3H2BB p16INK4A/p14ARFmRNA: miR-24NonendonucleolyticRISCMINK1 gene HIST1H2BO miR-24-2 HIST2H2AA3 HIST2H3A IFNB1p-T,Y-MAPK8 ATPMe3K-28-H3F3A p-S271,T275-MAP2K7 E2F2 ADPTFDP2 p-T182-MAPKAPK5 CDKN2D UBB(77-152) MAP3K5:TXNMINK1 ADPATPmiR-24NonendonucleolyticRISC2OGp-T,Y-MAPK8 CDKN2C HIST1H2BN p-T180,Y182-MAPK11 UBA52(1-76) p14ARFCDKN2A gene TNRC6B SUCCAp-p38MAPK:p-MAPKAPK2/3p-T,Y MAPK dimersHIST1H2AC H2AFJ HIST1H2BH Senescence-Associated Secretory Phenotype (SASP)HIST1H2BO ATPEED GeneADPTFDP1 PHC2 EZH2 Gene MOV10 RNF2 MINK1/TNIKPHC3 UBC(381-456) E2F3 TFDP1 RPS27A(1-76) AdoMetHIST1H2BJ HIST2H2AA3 JUNCDKN2AGene:H3K27Me3-NucleosomeMAPK10 MDM4 p-S,2T-MAPKAPK3 H2AFJ E2F2 p16INK4A mRNA MAPK8 CBX8 E2F3 Mitotic G1 phase andG1/S transitionp16INK4A TNRC6C CDK4 RNF2 SUZ12Gene:E2F1/2/3:DP1/2p-S189,T193-MAP2K3,p-S207,T211-MAP2K6p-S166,S188-MDM2dimer,p-S166,S188-MDM2:MDM4p-T185,Y187-MAPK1 MAPKAPK3 p-2S-cJUN:p-2S,2T-cFOS:KDM6B GeneHIST3H2BB p-MAP2K4/p-MAP2K7HIST1H2AJ phospho-p38 MAPK:MAPKAPK5p-S189,T193-MAP2K3 H2BFS SUZ12 GeneE2F2 UBC(305-380) HIST1H2AB CDKN2B Oncogenic MAPKsignalingp16INK4Ap-S207,T211-MAP2K6 p14ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53Me3K-28-H3F3A EED Gene PolyUb-TP53 AdoHcyATPHIST2H2BE HIST1H3A ADPMAP2K3 UBC(153-228) p-S,2T-MAPKAPK3 RBBP7 PRC2 (EZH2) CoreHIST1H2AD p-T180,Y182-MAPK14 p-S166,S188-MDM2dimer,p-S166,S188-MDM2,MDM4:TP53UBC(457-532) HIST1H2BA HIST1H2AB Fe2+MAPKAPK5 MAPKAPK5 H2AFX ADPADPPRC1.4MDM4 H2AFV HIST1H2BB TFDP1 p38 MAPK:MAPKAPK5EIF2C4 ATPMINK1/TNIK genesE2F2 p-S37-TP53 TetramerMAPK11 E2F3 p-T325,T331,S362,S374-FOS UBC(1-76) KDM6B Gene2xHC-TXNphospho-MAPKp38:p-MAPKAPK3H2BFS CBX4 Me3K-28-HIST1H3A EZH2Gene:E2F1/2/3:DP1/2H2AFJ CBX4 p-S257,T261-MAP2K4 p-S-BMI1 H2AFB1 HIST1H2BL H2AFB1 HIST1H2BN H2AFX ATPCDKN2A genep-MAPK8,9,10H2AFZ p-S189,T193-MAP2K3 E2F1 p-MAPK8,9,10DNA Damage/TelomereStress InducedSenescenceEIF2C1 KDM6B Gene p-S63,S73-JUNp-S63,S73-JUN p-2S-cJUN:p-2S,2T-cFOSMAPK14 MDM4 ATPCDKN2AGene:H3K27Me3-Nucleosome:PRC1.4CDKN2D MAP4K4 gene HIST2H2BE FOSMAPK14 ROSRNF2 CDKN2B ATPHIST1H2BM HIST1H2BC UBB(1-76) p-S166,S188-MDM2 p-T180,Y182-MAPK11 KDM6B H2AFV HIST1H2AC p-S37-TP53 HIST2H2AC CDK6 HIST1H2AJ HIST1H2BM EZH2HIST2H2AC EIF2C3 TP53 TetramerBMI1 Cell CycleCheckpointsMAP2K3,MAP2K6HIST1H2BN BMI1 TFDP2 E2F3 MAPKAPK2 H2AFV p-S166,S188-MDM2 HIST1H2AD TFDP1 PHC3 CDKN2A gene SCMH1-2 p-T180,Y182-MAPK11 CDK4,CDK6H2BFS p-T180,Y182-MAPK14 HIST1H2BA CBX6 HIST1H2BC SCMH1-2 ADPTFDP2 ADPHIST1H2BH HIST1H2BM TP53 p14ARF mRNA SUZ12UBC(77-152) miR-24-1 TXN MAPKAPK3 E2F1,E2F2,E2F3:TFDP1,TFDP2HIST1H2BH EED EZH2 RBBP7HIST1H2BB H3F3A MAP2K4p16INK4A mRNA MAP4K4 p-T183,Y185-MAPK9 RING1 HIST1H2BJ EIF2C3 CDKN2AGene:Nucleosomep38 MAPK:MAPKAPK2,3HIST1H2BL p-PRC1.4 complexPHC3 E2F1 TNRC6A CBX6 TFDP2 p-T180,Y182-MAPK14 p-T221,Y223-MAPK10 p-p38 MAPK:MAPKAPK2,3Fe2+ p-T325,T331,S362,S374-FOSHIST1H4 p-S207,T211-MAP2K6 UBB(153-228) Me3K-28-HIST2H3A CBX2 HIST1H2AJ PHC2 p-T221,Y223-MAPK10 HIST3H2BB HIST1H2BO MOV10 miR-24-1 CDKN2A gene TNRC6C p-T180,Y182-MAPK11 HIST1H2AC ADPKDM6BHIST2H2AC p-T180,Y182-MAPK14 HIST1H2AB MDM4 CBX2 TNRC6A H2AFB1 H2AFZ p16INK4A/p14ARF mRNAKDM6B:Fe2+PHC1 MAPK9 MAPKAPK2 RBBP4 MAP2K6 PHC1 H2AFX PolyUb-TP53 TetramerHIST1H2BC p-S166,S188-MDM2 p14ARF mRNA HIST1H2BK PHC2 Oncogene InducedSenescenceUBC(533-608) HIST1H2BA RING1 TNRC6B ATPEEDCBX6 MAPK11 p14ARF p14ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4p-T180,Y182-MAPK14 p-T325,T331,S362,S374-FOS Intrinsic Pathwayfor Apoptosis11, 27, 35, 36, 47...13, 16, 30, 43-45, 69...61, 65, 68, 72, 92...59, 87, 126, 1336, 8, 12, 14, 17...37, 48, 50, 51, 73...1815, 9935, 10911124, 42, 791152, 5928, 38, 63, 9341, 57, 67, 84, 1137, 21, 12858591877


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 p16INK4A and p14ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14ARF 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 p14ARF 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 p16INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).<p>
p16INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14ARF 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>


Pathway is converted from Reactome ID: 2559580
Reactome version: 73
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Reactome Author: Orlic-Milacic, Marija

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