Oncogene Induced Senescence (Homo sapiens)

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3, 4, 9, 11, 15...9, 3462955349666939648, 50, 53, 643, 17, 29, 37, 9455666693, 966211, 15, 38, 54nucleoplasmcytosolp14-ARF MDM2 p-T72-ETS2:ID1ADPp16-INK4A mRNAUb-TP53TFDP1 Cell CycleCheckpointsp-T202,Y204-MAPK3 MDM2 UBC(229-304) p-T38-ETS1/p-T72-ETS2UBB(153-228) Oxidative StressInduced SenescenceMitotic G1-G1/SphasesUBB(77-152) p16-INK4A mRNA p14-ARF mRNA UBC(77-152) RPS27A(1-76) SP1Cdk4/6:INK4A complexUBC(305-380) CDK4 ubiquitinCDKN2D UBC(609-684) ETS2 Genep16-INK4ap16-INK4a ETS2 Gene Intrinsic Pathwayfor ApoptosisDNA Damage/TelomereStress InducedSenescenceTP53 p14-ARFTP53 TetramerDP-1:E2F1/2/3TFDP1 CDKN2A Gene p-T72-ETS2 Ub-MDM2UBC(457-532) CDKN2A GeneERF ERF:ETS2 GeneETS1/ETS2TP53 CDK6 UBC(153-228) p-T72-ETS2 ATPUBA52(1-76) CDKN2C DP1/2: E2F1/2/3:SP1: CDKN2A GeneRAF/MAP kinasecascadeETS1 p14-ARF:MDM2SP1 UBC(1-76) ID1ETS2 TP53 p-T185,Y187-MAPK1 ERFUBB(1-76) p-T526-ERFID1 p-T,Y MAPK dimersMOV10 p-T38-ETS1/p-T72-ETS2:CDKN2AGeneCDKN2B p-T72-ETS2p-T526-ERFp14-ARF:MDM2:TP53MDM2 ATPCdk4/6MDM2:TP53MDM2 CDKN2A Gene p14-ARF p-T38-ETS1 p16-INK4a/p14-ARFmRNAETS2p16-INK4a/p14-ARFmRNA: miR-24NonendonucleolyticRISCMOV10 TP53 UBC(381-456) p14-ARF mRNAINK4AUBC(533-608) miR-24NonendonucleolyticRISCADP5, 6, 19, 22, 31...27, 51, 857, 8, 23, 44, 49...9, 3420, 52, 59, 719662661, 2, 10, 12-14, 16...


Description

Oncogene-induced senescence is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.

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.
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  109. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y.; ''Enhanced phosphorylation of p53 by ATM in response to DNA damage.''; PubMed Europe PMC Scholia
  110. Yu TW, Anderson D.; ''Reactive oxygen species-induced DNA damage and its modification: a chemical investigation.''; PubMed Europe PMC Scholia
  111. Parry D, Bates S, Mann DJ, Peters G.; ''Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.''; PubMed Europe PMC Scholia
  112. Mizukami Y, Yoshioka K, Morimoto S, Yoshida Ki.; ''A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.''; PubMed Europe PMC Scholia
  113. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D.; ''Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein.''; PubMed Europe PMC Scholia
  114. Momand J, Zambetti GP, Olson DC, George D, Levine AJ.; ''The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114856view16:36, 25 January 2021ReactomeTeamReactome version 75
113302view11:37, 2 November 2020ReactomeTeamReactome version 74
112514view15:47, 9 October 2020ReactomeTeamReactome version 73
101426view11:30, 1 November 2018ReactomeTeamreactome version 66
100964view21:07, 31 October 2018ReactomeTeamreactome version 65
100501view19:42, 31 October 2018ReactomeTeamreactome version 64
100047view16:25, 31 October 2018ReactomeTeamreactome version 63
99599view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93939view13:46, 16 August 2017ReactomeTeamreactome version 61
93528view11:26, 9 August 2017ReactomeTeamreactome version 61
88060view14:01, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
88059view14:01, 25 July 2016RyanmillerOntology Term : 'cellular senescence pathway' added !
86627view09:22, 11 July 2016ReactomeTeamreactome version 56
83246view10:29, 18 November 2015ReactomeTeamVersion54
81351view12:52, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDK6 ProteinQ00534 (Uniprot-TrEMBL)
CDKN2A Gene ProteinENSG00000147889 (Ensembl)
CDKN2A GeneGeneProductENSG00000147889 (Ensembl)
CDKN2B ProteinP42772 (Uniprot-TrEMBL)
CDKN2C ProteinP42773 (Uniprot-TrEMBL)
CDKN2D ProteinP55273 (Uniprot-TrEMBL)
Cdk4/6:INK4A complexComplexR-HSA-182579 (Reactome)
Cdk4/6ComplexR-HSA-69209 (Reactome)
Cell Cycle CheckpointsPathwayR-HSA-69620 (Reactome) A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.

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.

DNA Damage/Telomere

Stress Induced

Senescence		PathwayR-HSA-2559586 (Reactome) Reactive oxygen species (ROS), whose concentration increases in senescent cells due to oncogenic RAS-induced mitochondrial dysfunction (Moiseeva et al. 2009) or due to environmental stress, cause DNA damage in the form of double strand breaks (DSBs) (Yu and Anderson 1997). In addition, persistent cell division fueled by oncogenic signaling leads to replicative exhaustion, manifested in critically short telomeres (Harley et al. 1990, Hastie et al. 1990). Shortened telomeres are no longer able to bind the protective shelterin complex (Smogorzewska et al. 2000, de Lange 2005) and are recognized as damaged DNA.

The 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.

DP-1:E2F1/2/3ComplexR-HSA-1227905 (Reactome)
DP1/2: E2F1/2/3: SP1: CDKN2A GeneComplexR-HSA-3209097 (Reactome)
ERF ProteinP50548 (Uniprot-TrEMBL)
ERF:ETS2 GeneComplexR-HSA-3209182 (Reactome)
ERFProteinP50548 (Uniprot-TrEMBL)
ETS1 ProteinP14921 (Uniprot-TrEMBL)
ETS1/ETS2ComplexR-HSA-3132719 (Reactome)
ETS2 Gene ProteinENSG00000157557 (Ensembl)
ETS2 GeneGeneProductENSG00000157557 (Ensembl)
ETS2 ProteinP15036 (Uniprot-TrEMBL)
ETS2ProteinP15036 (Uniprot-TrEMBL)
ID1 ProteinP41134 (Uniprot-TrEMBL)
ID1ProteinP41134 (Uniprot-TrEMBL)
INK4AComplexR-HSA-182588 (Reactome)
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

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.

MDM2 ProteinQ00987 (Uniprot-TrEMBL)
MDM2:TP53ComplexR-HSA-69489 (Reactome)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome)
Oxidative Stress Induced SenescencePathwayR-HSA-2559580 (Reactome) 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).

RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
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).
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SP1 ProteinP08047 (Uniprot-TrEMBL)
SP1ProteinP08047 (Uniprot-TrEMBL)
TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-MDM2ComplexR-HSA-3215303 (Reactome)
Ub-TP53ComplexR-HSA-3209186 (Reactome)
miR-24

Nonendonucleolytic

RISC		ComplexR-HSA-3209134 (Reactome) The RNA-induced silencing complex contains an Argonaute (AGO) protein, whose PAZ domain binds the 3' end of the miRNA. The PIWI domain of AGO is responsible for cleavage of target RNAs, that is, RNAs complementary to the miRNA. Only AGO2 (EIF2C2) is capable of cleavage, however. AGO1 (EIF2C1), AGO3 (EIF2C3), and AGO4 (EIF2C4) repress translation of target RNAs by binding without cleavage. In vivo, cleavage by AGO2 and repression of translation by all AGOs require interaction with a TNRC6 protein (GW182 protein) and MOV10. The interaction with TNRC6 proteins is also responsible for localizing the AGO complex to Processing Bodies (P-bodies). Tethering of the C-terminal domain of a TNRC6 protein to a mRNA is sufficient to cause repression of translation.
p-T,Y MAPK dimersComplexR-HSA-198701 (Reactome)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T38-ETS1 ProteinP14921 (Uniprot-TrEMBL)
p-T38-ETS1/

p-T72-ETS2:CDKN2A

Gene		ComplexR-HSA-3200029 (Reactome)
p-T38-ETS1/ p-T72-ETS2ComplexR-HSA-3132724 (Reactome)
p-T526-ERFProteinP50548 (Uniprot-TrEMBL)
p-T72-ETS2 ProteinP15036 (Uniprot-TrEMBL)
p-T72-ETS2:ID1ComplexR-HSA-3209172 (Reactome)
p-T72-ETS2ProteinP15036 (Uniprot-TrEMBL)
p14-ARF ProteinQ8N726 (Uniprot-TrEMBL)
p14-ARF mRNA ProteinENST00000579755 (Ensembl)
p14-ARF mRNARnaENST00000579755 (Ensembl)
p14-ARF:MDM2:TP53ComplexR-HSA-3209189 (Reactome)
p14-ARF:MDM2ComplexR-HSA-3209192 (Reactome)
p14-ARFProteinQ8N726 (Uniprot-TrEMBL)
p16-INK4A mRNA ProteinENST00000304494 (Ensembl)
p16-INK4A mRNARnaENST00000304494 (Ensembl)
p16-INK4a ProteinP42771 (Uniprot-TrEMBL)
p16-INK4a/p14-ARF

mRNA: miR-24 Nonendonucleolytic

RISC		ComplexR-HSA-3209131 (Reactome)
p16-INK4a/p14-ARF mRNAComplexR-HSA-3209130 (Reactome)
p16-INK4aProteinP42771 (Uniprot-TrEMBL)
ubiquitinComplexR-HSA-68524 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-3132737 (Reactome)
ADPArrowR-HSA-3209160 (Reactome)
ATPR-HSA-3132737 (Reactome)
ATPR-HSA-3209160 (Reactome)
CDKN2A GeneR-HSA-3200023 (Reactome)
CDKN2A GeneR-HSA-3209096 (Reactome)
CDKN2A GeneR-HSA-3209098 (Reactome)
CDKN2A GeneR-HSA-3209109 (Reactome)
Cdk4/6:INK4A complexArrowR-HSA-182594 (Reactome)
Cdk4/6R-HSA-182594 (Reactome)
DP-1:E2F1/2/3R-HSA-3209096 (Reactome)
DP1/2: E2F1/2/3: SP1: CDKN2A GeneArrowR-HSA-3209096 (Reactome)
DP1/2: E2F1/2/3: SP1: CDKN2A GeneArrowR-HSA-3209109 (Reactome)
ERF:ETS2 GeneArrowR-HSA-3209177 (Reactome)
ERF:ETS2 GeneTBarR-HSA-3209179 (Reactome)
ERFR-HSA-3209160 (Reactome)
ERFR-HSA-3209177 (Reactome)
ETS1/ETS2R-HSA-3132737 (Reactome)
ETS2 GeneR-HSA-3209177 (Reactome)
ETS2 GeneR-HSA-3209179 (Reactome)
ETS2ArrowR-HSA-3209179 (Reactome)
ID1R-HSA-3209165 (Reactome)
INK4AR-HSA-182594 (Reactome)
MDM2:TP53R-HSA-3209185 (Reactome)
MDM2:TP53R-HSA-3209195 (Reactome)
MDM2:TP53mim-catalysisR-HSA-3209195 (Reactome)
R-HSA-182594 (Reactome) Prior to mitogen activation, the inhibitory proteins, INK4 (p15, p16, p18, and p19) associate with the catalytic domain of free CDK4/6, preventing its association with cyclins, and thus its activation.
R-HSA-3132737 (Reactome) Both ETS1 and ETS2 contain a consensus site (PLLTP) for MAPK3 and MAPK1 (ERK1 and ERK2, respectively) in the vicinity of the pointed domain, while the pointed domain contains a docking site needed for ERK1/2 binding to ETS1/2. ETS1 and ETS2 are able to collaborate with RAS in superactivating the promoters that contain RREs (RAS response elements) that include ETS-binding sites. The cooperation of ETS1 and ETS2 with RAS activation is dependent on the phosphorylation of PLLTP threonine residue (T38 in ETS1; T72 in ETS2) (Yang et al. 1996, Seidel et al. 2002). Phosphorylation of ETS1 and ETS2 by ERK1/2 induces a conformational change that increases their affinity for the TAZ domain of the transcriptional coactivator CREBBP (CBP) and the transcriptional activation of RREs (Foulds et al. 2004, Nelson et al. 2010), although ETS1/ETS2 may interact with CREBBP in the absence of phosphorylation (Jayaraman et al. 1999). Phosphorylation of serine residue S41 of ETS1 (corresponds to serine residue S75 of ETS2) may be necessary for full activation of ETS1/2 (Nelson et al. 2010).
R-HSA-3200023 (Reactome) ETS1 and ETS2, activated by RAS/RAF/MAP kinase cascade, bind the promoter of p16-INK4A in the CDKN2A locus (Ohtani et al. 2001). CDKN2A locus also encodes p14-ARF (p19-ARF in mouse), but from a different promoter and in a different reading frame. While p16-INK4A and p19-ARF use different exon 1, (exon 1-alpha and exon 1-beta, respectively), they share exons 2 and 3. However, because the reading frames are different, there is no amino acid sequence similarity between the two proteins.
R-HSA-3209096 (Reactome) E2F1, E2F2 or E2F3 forms a complex with the transcription factor SP1 on p14-ARF promoter (Parisi et al. 2002).
R-HSA-3209098 (Reactome) Phosphorylated ETS1 and ETS2 stimulate p16-INK4A transcription, resulting in cell cycle arrest with arrested cells exhibiting high p16-INK4A level and senescence-associated beta-galactosidase activity. It is possible that ETS2 is the main transmitter of RAS signaling to p16-INK4A at the initiation of the senescence program, and that ETS1 maintains high p16-INK4A level once the senescence is already established (Ohtani et al. 2001).
R-HSA-3209109 (Reactome) E2F1, E2F2 or E2F3 in complex with SP1 stimulates p14-ARF transcription (Parisi et al. 2002). Therefore, increased activity of E2F1, E2F2 or E2F3, which may result from the loss of function of the tumor suppressor protein RB1, an inhibitor of E2F1/2/3, leads to an increased level of p14-ARF.
R-HSA-3209111 (Reactome) MicroRNA miR-24 inhibits translation of p14-ARF mRNA without causing mRNA degradation. This results in high p14-ARF transcript level accompanied by low p14-ARF protein level (To et al. 2012).
R-HSA-3209114 (Reactome) MicroRNA miR-24 inhibits translation of p16-INK4A mRNA without causing mRNA degradation. This results in high p16-INK4A transcript level accompanied by low p16-INK4A protein level (Lal et al. 2008).
R-HSA-3209151 (Reactome) MicroRNA miR-24 is able to bind both p16-INK4A mRNA (Lal et al. 2008) and p14-ARF mRNA (To et al. 2012) through their shared 3'UTR. miR-24 inhibits translation of p16-INK4A and p14-ARF mRNAs, but does not induce mRNA degradation, resulting in expression of high levels of p16-INK4A and p14-ARF transcripts, while protein levels of p16-INK4A and p14-ARF are low (Lal et al. 2008, To et al. 2012).
R-HSA-3209159 (Reactome) Phosphorylation of ERF at threonine T526 by activated ERKs triggers ERF export from the nucleus to the cytosol (Le Gallic et al. 2004), which is expected to relieve ERF-mediated inhibition of ETS2 transcription.
R-HSA-3209160 (Reactome) Activated ERKs (ERK1 i.e. MAPK3 and ERK2 i.e. MAPK1) phosphorylate ERF on threonine residue T526 and possibly other sites. The threonine T526 seems to be the dominant phosphorylation site and its functional relevance has been established (Sgouras et al. 1995, Le Gallic et al. 2004).
R-HSA-3209165 (Reactome) Binding of ID1 to ETS2 inhibits ETS2-mediated activation of p16-INK4A transcription (Ohtani et al. 2001).
R-HSA-3209177 (Reactome) ERF binds to an ETS-binding site in the ETS2 promoter (Sgouras et al. 1995).
R-HSA-3209179 (Reactome) Binding of ERF to ETS2 promoter strongly represses ETS2 transcription (Sgouras et al. 1995).
R-HSA-3209185 (Reactome) p14-ARF forms a complex with TP53-bound MDM2 by interacting with the C-terminus of MDM2, while the N-terminus of MDM2 is involved in TP53 (p53) binding. p14-ARF cannot associate with TP53 in the absence of MDM2 (Zhang et al. 1998).
R-HSA-3209195 (Reactome) MDM2 is a ubiquitin ligase whose expression is positively regulated by TP53 (p53) (Wu et al. 1993). MDM2 binds TP53 tetramer (Maki 1999) and promotes its ubiquitination and subsequent degradation (Fuchs et al. 1998). Along with ubiquitinating TP53, MDM2 also autoubiqutinates (Fang et al. 2000)
R-HSA-69886 (Reactome) Binding of p14-ARF to MDM2 decreases the half-life of MDM2, likely through promoting MDM2 degradation. Thus, p14-ARF inhibits MDM2-mediated ubiquitination and degradation of TP53 (Zhang et al. 1998).
SP1R-HSA-3209096 (Reactome)
TP53 TetramerArrowR-HSA-69886 (Reactome)
Ub-MDM2ArrowR-HSA-3209195 (Reactome)
Ub-TP53ArrowR-HSA-3209195 (Reactome)
miR-24

Nonendonucleolytic

RISC		R-HSA-3209151 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-3132737 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-3209160 (Reactome)
p-T38-ETS1/

p-T72-ETS2:CDKN2A

Gene		ArrowR-HSA-3200023 (Reactome)
p-T38-ETS1/

p-T72-ETS2:CDKN2A

Gene		ArrowR-HSA-3209098 (Reactome)
p-T38-ETS1/ p-T72-ETS2ArrowR-HSA-3132737 (Reactome)
p-T38-ETS1/ p-T72-ETS2R-HSA-3200023 (Reactome)
p-T526-ERFArrowR-HSA-3209159 (Reactome)
p-T526-ERFArrowR-HSA-3209160 (Reactome)
p-T526-ERFR-HSA-3209159 (Reactome)
p-T72-ETS2:ID1ArrowR-HSA-3209165 (Reactome)
p-T72-ETS2R-HSA-3209165 (Reactome)
p14-ARF mRNAArrowR-HSA-3209109 (Reactome)
p14-ARF mRNAR-HSA-3209111 (Reactome)
p14-ARF:MDM2:TP53ArrowR-HSA-3209185 (Reactome)
p14-ARF:MDM2:TP53R-HSA-69886 (Reactome)
p14-ARF:MDM2ArrowR-HSA-69886 (Reactome)
p14-ARFArrowR-HSA-3209111 (Reactome)
p14-ARFR-HSA-3209185 (Reactome)
p16-INK4A mRNAArrowR-HSA-3209098 (Reactome)
p16-INK4A mRNAR-HSA-3209114 (Reactome)
p16-INK4a/p14-ARF

mRNA: miR-24 Nonendonucleolytic

RISC		ArrowR-HSA-3209151 (Reactome)
p16-INK4a/p14-ARF

mRNA: miR-24 Nonendonucleolytic

RISC		TBarR-HSA-3209111 (Reactome)
p16-INK4a/p14-ARF

mRNA: miR-24 Nonendonucleolytic

RISC		TBarR-HSA-3209114 (Reactome)
p16-INK4a/p14-ARF mRNAR-HSA-3209151 (Reactome)
p16-INK4aArrowR-HSA-3209114 (Reactome)
ubiquitinR-HSA-3209195 (Reactome)

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP3308"
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