Oncogene Induced Senescence

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Homo sapiens
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Oncogene-induced senescence (OIS) 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: p16INK4A and p14ARF. p16INK4A and p14ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). 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. p16INK4A 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 p16INK4A 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, p15INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15INK4B, together with p16INK4A, 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 p15INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15INK4B 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 p16INK4A 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 p16INK4A transcription (Ohtani et al. 2004).

Transcription of p14ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14ARF 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.
While OIS has been studied to considerable detail in cultured cells, establishment of in vivo role of OIS has been difficult due to lack of specific biomarkers and its interconnectedness with other senescence pathways (Baek and Ryeom 2017, reviewed in Sharpless and Sherr 2015).

Literature References
PubMed ID Title Journal Year
12839923 Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model

Lee, J, Glick, AB, Vijayachandra, K

Cancer Res. 2003
22336108 Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma development

Thériault, BL, Gallie, BL, To, KH, Pajovic, S

BMC Cancer 2012
11782450 An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors

Graves, BJ, Seidel, JJ

Genes Dev. 2002
20583212 Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth

Mumcuoglu, M, Ozturk, M, Cingoz, B, Senturk, S, Gursoy-Yuzugullu, O, Akcali, KC

Hepatology 2010
11234019 Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence

Sharrocks, AD, Peters, G, Ohashi, Y, Sugimoto, M, Zebedee, Z, Ohtani, N, Huot, TJ, Hara, E, Stinson, JA

Nature 2001
7588608 ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation

Mavrothalassitis, GJ, Fisher, RJ, Blair, DG, Athanasiou, MA, Beal, GJ, Sgouras, DN

EMBO J. 1995
20534573 Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP

Graves, BJ, Lee, GM, Kang, HS, Nelson, ML, Blaszczak, AG, Lau, DK, McIntosh, LP

Proc. Natl. Acad. Sci. U.S.A. 2010
18365017 p16(INK4a) translation suppressed by miR-24

Yang, X, Pullmann, R, Gorospe, M, Dykxhoorn, D, Lal, A, Martindale, JL, Abdelmohsen, K, Srikantan, S, Subrahmanyam, R, Lieberman, J, Kim, HH, Kuwano, Y, Ahmed, F, Navarro, F

PLoS ONE 2008
8259215 A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4

Hannon, GJ, Serrano, M, Beach, D

Nature 1993
8521522 Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest

Quelle, DE, Ashmun, RA, Zindy, F, Sherr, CJ

Cell 1995
9704925 Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence

Sangfelt, O, Erickson, S, Grandér, D, Castro, J, Heyman, M, Einhorn, S

Oncogene 1998
8319905 The p53-mdm-2 autoregulatory feedback loop

Levine, AJ, Olson, D, Bayle, JH, Wu, X

Genes Dev. 1993
27812880 Detection of Oncogene-Induced Senescence In Vivo

Baek, KH, Ryeom, S

Methods Mol. Biol. 2017
15572696 Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment

Graves, BJ, Foulds, CE, Nelson, ML, Blaszczak, AG

Mol. Cell. Biol. 2004
8552081 Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2

Yang, BS, Stacey, KJ, Hauser, CA, Hume, DA, Ostrowski, MC, Van Beveren, C, Maki, RA, Henkel, G, Colman, MS

Mol. Cell. Biol. 1996
9529249 ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways

Zhang, Y, Xiong, Y, Yarbrough, WG

Cell 1998
14729966 ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression

Cohen, P, Mavrothalassitis, G, Le Gallic, L, Biteau, B, Virgilio, L

Mol. Cell. Biol. 2004
10722742 Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53

Vousden, KH, Weissman, AM, Jensen, JP, Ludwig, RL, Fang, S

J. Biol. Chem. 2000
11883935 Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors

Parisi, T, Calabrò, V, La Mantia, G, Pollice, A, Di Cristofano, A

Biochem. Biophys. Res. Commun. 2002
9824166 Mdm2 association with p53 targets its ubiquitination

Fuchs, SY, Adler, V, Ronai, Z, Wu, X, Buschmann, T

Oncogene 1998
10733595 Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b)

Malumbres, M, Corral, T, Pérez De Castro, I, Pellicer, A, Hernández, MI, Jimenez, M

Mol. Cell. Biol. 2000
26105537 Forging a signature of in vivo senescence

Sharpless, NE, Sherr, CJ

Nat. Rev. Cancer 2015
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