Reactome: A Curated Pathway Database

Oxidative Stress Induced Senescence

Stable Identifier
Homo sapiens
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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.

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).

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).

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).

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).

Literature References
PubMed ID Title Journal Year
19451217 The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence Genes Dev. 2009
22020331 Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis Oncogene 2012
17254968 PRAK is essential for ras-induced senescence and tumor suppression Cell 2007
14532106 EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer EMBO J. 2003
11564866 Use of chromatin immunoprecipitation to clone novel E2F target promoters Mol. Cell. Biol. 2001
16337592 Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells Mol. Cell 2005
15287722 Catalysis and function of the p38 alpha.MK2a signaling complex Biochemistry 2004
12808055 Regulation of PRAK subcellular location by p38 MAP kinases Mol. Biol. Cell 2003
17210787 pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene Genes Dev. 2007
12189133 Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade J. Biol. Chem. 2002
7816143 Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA Nature 1995
9628874 PRAK, a novel protein kinase regulated by the p38 MAP kinase EMBO J. 1998
9162092 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. J Biol Chem 1997
19528227 Mitochondrial dysfunction contributes to oncogene-induced senescence Mol. Cell. Biol. 2009
16436515 DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation Mol. Biol. Cell 2006
22325352 PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes Mol. Cell 2012
12134156 Molecular interpretation of ERK signal duration by immediate early gene products Nat Cell Biol 2002
7588633 The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells EMBO J 1995
8846784 Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2 EMBO J 1995
17344414 The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells Genes Dev. 2007
9030721 Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agents Eur J Biochem 1997
8774846 A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress FEBS Lett. 1996
8626550 Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase J. Biol. Chem. 1996
9529249 ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways Cell 1998
12435631 Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein Genes Dev 2002
12171911 Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export J Biol Chem 2002
9195981 A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion. J Biol Chem 1997
17332741 Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus EMBO J. 2007
8622688 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region Mol. Cell. Biol. 1996
17395714 Molecular basis of MAPK-activated protein kinase 2:p38 assembly Proc Natl Acad Sci U S A 2007
9564042 Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1 EMBO J. 1998
8259215 A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 Nature 1993
19451218 Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS Genes Dev. 2009
8974401 Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways Science 1997
15563468 MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1 J. Biol. Chem. 2005
19462008 Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence PLoS ONE 2009
11062067 Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7 Biochem J 2000
15866172 Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases Mol. Cell 2005
8622669 MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway Mol Cell Biol 1996
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