Oxidative Stress Induced Senescence (Homo sapiens)

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5, 10, 15, 17, 19...3335101, 12312443, 61, 75, 1036336, 51, 1426335687548, 552233, 124, 12676757119, 12515, 10134, 74, 8676, 1086810, 13, 18, 97, 13617, 31, 71, 8810837, 47, 49, 62, 69...84, 8832, 52635, 1143221, 27, 40, 91, 94...3143, 103, 121, 12663122, 12938, 59, 92, 115, 137121, 12644, 84mitochondrial matrixcytosolnucleoplasmSUCCAp-S189,T193-MAP2K3 CDKN2C Me3K-28-H3F3A UBB(153-228) p-2S-cJUN:p-2S,2T-cFOS:KDM6B GeneHIST1H2AB AdoMetUBC(229-304) TNIK gene p-T221,Y223-MAPK10 MDM4 CBX8 p-T,Y MAPK dimersCBX6 CBX6 BMI1 ADPH2BFS Mitotic G1-G1/SphasesATPPHC2 p-T185,Y187-MAPK1 MAPK8 TFDP2 RING1 CDKN2AGene:H3K27Me3-NucleosomeH2AFZ Me3K-28-HIST1H3A p14-ARF mRNATNRC6C HIST1H2BO p-S,2T-MAPKAPK3 HIST1H2AD CBX2 Me3K-28-H3F3A p16-INK4A mRNA HIST2H2AC HIST1H2AD AdoHcyMINK1/TNIKCDK6 RING1 H2AFV MAP4K4 gene phospho-MAPKp38:p-MAPKAPK3p-S63,S73-JUN HIST1H2BO E2F1 MINK1 gene EZH2 HIST1H2BB MAPK11 PHC2 MOV10 CDKN2A geneSUZ12 Gene p-T180,Y182-MAPK11 H2AFB1 ADPCBX4 CDKN2A gene MAPK8,9,10H2BFS ATPCBX8 UBC(153-228) MAPKAPK5 HIST1H2AJ p-T180,Y182-MAPK14 MAP2K3 MAPKAPK2 HIST1H2AD CDKN2B EED Gene ATPADPPHC3 TNIK TFDP1 CDKN2AGene:H3K27Me3-Nucleosome:PRC1.4CDKN2AGene:NucleosomeE2F3 HIST1H2BC HIST1H2BO EED CDK6 miR-24-2 p-T180,Y182-MAPK11 TNRC6A E2F2 p-T183,Y185-MAPK9 HIST1H2BN IFNB1RBBP7miR-24-1 CDK4 HIST1H2BL HIST3H2BB MAPKAPK5 KDM6B Gene p16-INK4a/p14-ARFmRNAH2AFJ 2OGCBX4 HIST1H2AB TP53 UBB(77-152) PHC1 H2AFV p-S166,S188-MDM2 HIST2H2BE MAPK10 HIST1H2BD phospho-p38MAPK:p-T-182-MAPKAPK5H2AFJ TNRC6B PolyUb-TP53 TetramerSUZ12 GeneSCMH1-2 p-S63,S73-JUNHIST1H2AC Oncogenic MAPKsignalingCBX6 KDM6BMe3K-28-HIST2H3A HIST1H2AC INK4UBC(533-608) H2AFX TP53 HIST1H4 HIST1H3A Intrinsic Pathwayfor Apoptosisp38 MAPK:MAPKAPK5ADPMAPK11 MINK1 HIST1H2BD FOSE2F2 Fe2+ MAP3K5 p-MAP2K4/p-MAP2K7EIF2C4 HIST1H2AJ HIST1H2BJ MDM4 SCMH1-2 HIST1H2BK PHC2 EEDHIST1H2BA PHC3 H2AFZ TXN p-S63,S73-JUN p-2S-cJUN:p-2S,2T-cFOSp-p38 MAPK:MAPKAPK2,3CDKN2A gene KDM6B GeneHIST1H2BB EIF2C3 p-S257,T261-MAP2K4Senescence-Associated Secretory Phenotype (SASP)ROSCDKN2D HIST2H2AC Fe2+E2F3 MAP2K3,MAP2K6CBX8 UBC(457-532) PolyUb-TP53 RBBP7 p-T182-MAPKAPK5 TNRC6B p-S189,T193-MAP2K3,p-S207,T211-MAP2K6HIST2H2AA3 HIST1H2BL HIST2H2AA3 UBC(381-456) HIST1H2BM CDKN2D p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4MAP2K6 p38 MAPK:MAPKAPK2,3ADPMAP4K4 Me3K-28-HIST1H3A CDK4 E2F1,E2F2,E2F3:TFDP1,TFDP2p16-INK4ap-T221,Y223-MAPK10 p-T222,S272,T334-MAPKAPK2 DNA Damage/TelomereStress InducedSenescenceHIST1H2BC TNRC6A CDKN2B MAPKAPK3 JUNHIST2H2BE RNF2 TP53 TetramerSUZ12HIST2H2BE p-T180,Y182-MAPK11 p14-ARF p-S37-TP53 MDM4 CDKN2A gene p-S166,S188-MDM2 p16-INK4a/p14-ARFmRNA: miR-24NonendonucleolyticRISCMAPKAPK3 ATPEED GeneSUZ12Gene:E2F1/2/3:DP1/2EIF2C4 HIST1H2BJ E2F1 EEDGene:E2F1/2/3:DP1/2HIST1H2BD HIST1H2BM ADPE2F1 CDK4,CDK6:INK4miR-24-1 ATPEIF2C1 p-S166,S188-MDM2 miR-24NonendonucleolyticRISCp-T325,T331,S362,S374-FOS EZH2Gene:E2F1/2/3:DP1/2HIST1H2BB ATPHIST1H2AJ H2AFX p16-INK4a HIST1H2AB ATPp14-ARF E2F2 ADPHIST1H4 p-S,2T-MAPKAPK3 MINK1/TNIK genesH2AFX HIST1H2BM H2AFZ Cell CycleCheckpointsp-S257,T261-MAP2K4 p-S166,S188-MDM2dimer,p-S166,S188-MDM2,MDM4:TP53p-T183,Y185-MAPK9 HIST1H2BN ADPATPCDKN2C SUZ12 miR-24-2 p-T180,Y182-MAPK14 HIST1H2BK HIST1H2BK p16-INK4a EZH2 GeneRBBP4TFDP1 HIST2H3A HIST1H2BH HIST2H2AA3 MAP2K4HIST3H2BB EZH2 Gene CBX2 ATPHIST1H4 CBX2 MAPK9 H2AFB1 H2AFJ TFDP1 EIF2C3 SCMH1-2 Ubp-S207,T211-MAP2K6 HIST1H2BA p-p38MAPK:p-MAPKAPK2/3E2F1 MOV10 p-S166,S188-MDM2dimer,p-S166,S188-MDM2:MDM4E2F3 p-S207,T211-MAP2K6 BMI1 HIST1H2BC p-S189,T193-MAP2K3,p-S207,T211-MAP2K6UBA52(1-76) PHC3 MAPK14 H2BFS EZH2TNRC6C 2xHC-TXNp-S271,T275-MAP2K7 TFDP2 p-PRC1.4 complexHIST3H2BB MDM4 phospho-p38 MAPK:MAPKAPK5TFDP2 RBBP4 HIST2H2AC p-MAPK8,9,10RING1 ADPHIST1H2BJ HIST1H2AC p-T180,Y182-MAPK14 KDM6B:Fe2+PRC2 (EZH2) CoreCDK4,CDK6p-T325,T331,S362,S374-FOS HIST1H2BH RPS27A(1-76) p-T,Y-MAPK8 TFDP2 p-T180,Y182-MAPK14 H2AFV ATPE2F2 CBX4 KDM6B TP53 p-S37-TP53 TetramerHIST1H2BA UBC(77-152) ATPMe3K-28-HIST2H3A p14-ARF mRNA E2F3 p-S166,S188-MDM2 p14-ARF mRNA ADPp-MAPK8,9,10MAPK14 MAP3K5p-S189,T193-MAP2K3 p16-INK4A mRNA MAP3K5:TXNMAPKAPK2 TFDP1 p14-ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4:TP53p-T202,Y204-MAPK3 HIST1H2BN UBC(305-380) RNF2 EIF2C1 p-T,Y-MAPK8 UBC(609-684) UBC(1-76) p-T180,Y182-MAPK11 PHC1 H3F3A p-S-BMI1 p16-INK4A mRNARNF2 Oncogene InducedSenescenceHIST1H2BH PRC1.4p-T180,Y182-MAPK11 HIST1H2BL p-T180,Y182-MAPK14 ADPPHC1 p-T325,T331,S362,S374-FOSp14-ARFH2AFB1 UBB(1-76) 617, 20, 25, 53, 67...14, 56, 57, 64, 70...2, 8-10, 26...12, 29, 41, 42, 54...76, 108521, 6, 85, 13511, 22, 82, 98, 11239, 46, 78636845, 61173343, 61, 75, 1033, 4, 10, 13, 16...24, 80, 9063121, 126


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>


Pathway is converted from Reactome ID: 2559580
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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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


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)