Oxidative Stress Induced Senescence (Homo sapiens)
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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).
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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.
Stress Induced
SenescenceThe 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.
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.
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. 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.
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this 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 (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
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.
Nonendonucleolytic
RISCmRNA: miR-24 Nonendonucleolytic
RISCAnnotated Interactions
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).
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.
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.
Nonendonucleolytic
RISCmRNA: miR-24 Nonendonucleolytic
RISCmRNA: miR-24 Nonendonucleolytic
RISCmRNA: miR-24 Nonendonucleolytic
RISC