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. 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)

external resources
NCBI:1270428
REACTOME:R-HSA-2559580
PUBMED:17344414
PUBMED:17332741
PUBMED:8622688
PUBMED:7588633
PUBMED:15563468
PUBMED:15287722
PUBMED:11062067
PUBMED:16337592
PUBMED:14532106
PUBMED:17254968
PUBMED:15866172
PUBMED:9628874
PUBMED:12171911
PUBMED:7816143
PUBMED:22020331
PUBMED:11564866
PUBMED:9162092
PUBMED:8974401
PUBMED:19451217
PUBMED:12808055
PUBMED:17210787
PUBMED:8846784
PUBMED:19462008
PUBMED:12134156
PUBMED:8626550
PUBMED:8774846
PUBMED:12189133
PUBMED:9195981
PUBMED:8622669
PUBMED:8259215
PUBMED:19528227
PUBMED:9564042
PUBMED:9529249
PUBMED:16436515
PUBMED:19451218
PUBMED:17395714
PUBMED:9030721
PUBMED:12435631
PUBMED:22325352

genes
BMI1 , CDK4 , CDK6 , CDKN2A , CDKN2B , CDKN2C , CDKN2D , MAPK14 , E2F1 , E2F2 , E2F3 , PHC1 , PHC2 , EZH2 , FOS , HIST1H2AE , HIST1H2AD , H2AFX , H2AFZ , HIST1H2BD , HIST1H2BB , H3F3A , H3F3B , IFNB1 , JUN , MDM2 , MDM4 , MAP3K5 , MOV10 , MAPK1 , MAPK3 , MAPK8 , MAPK11 , MAPK9 , MAPK10 , MAP2K3 , MAP2K6 , MAP2K7 , RBBP4 , RBBP7 , RING1 , RNF2 , RPS27A , MAP2K4 , TFDP1 , TFDP2 , TP53 , TXN , UBA52 , UBB , UBC , MAPKAPK3 , HIST1H4I , HIST1H2AJ , HIST1H2AC , HIST1H2AB , HIST2H2AA3 , HIST2H2AC , HIST1H2BG , HIST1H2BL , HIST1H2BN , HIST1H2BM , HIST1H2BF , HIST1H2BE , HIST1H2BH , HIST1H2BI , HIST1H2BC , HIST1H2BO , HIST2H2BE , HIST1H3A , HIST1H3D , HIST1H3C , HIST1H3E , HIST1H3I , HIST1H3G , HIST1H3J , HIST1H3H , HIST1H3B , HIST1H4A , HIST1H4D , HIST1H4F , HIST1H4K , HIST1H4J , HIST1H4C , HIST1H4H , HIST1H4B , HIST1H4E , HIST1H4L , HIST2H4A , CBX4 , MAPKAPK5 , EED , HIST1H3F , HIST1H2BJ , MAPKAPK2 , MAP4K4 , SCMH1 , TNIK , TNRC6B , KDM6B , CBX6 , SUZ12 , AGO1 , TNRC6A , MINK1 , H2AFJ , CBX8 , TNRC6C , PHC3 , CBX2 , HIST1H2BK , H2AFV , HIST4H4 , HIST2H3C , HIST3H2BB , AGO3 , AGO4 , HIST1H2BA , HIST2H3A , H2AFB1 , HIST2H4B , HIST2H3D , HIST2H2AA4 , MIR3605 , MIR4738 ,