Evasion of Oxidative Stress Induced Senescence Due to p16INK4A Defects

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R-HSA-9632693
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Homo sapiens
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The CDKN2A gene consists of four exons, exon 1beta, exon 1alpha, exon 2 and exon 3, going from the proximal to the distal gene end. There are two promoters in the CDKN2A gene locus. The promoter located between exons 1beta and 1alpha regulates transcription of the p16INK4A mRNA, which consists of exon 1alpha, exon 2 and exon 3 (only partially translated), and encodes a cyclin-dependent kinase inhibitor p16INK4A (also known as CDKN2A isoform 1, p16, INK4A, CDKN2A, CDK4I or MTS-1). The promoter located upstream of exon 1beta regulates transcription of the p14ARF mRNA, which consists of exon 1beta, exon 2 (partially translated) and exon 3 (untranslated). The p14ARF mRNA is translated in a different reading frame from the p16INK4A mRNA and produces the tumor suppressor ARF (also known as p14ARF or CDKN2A isoform 4), an inhibitor of MDM2 E3 ubiquitin ligase-mediated degradation of TP53 (p53).
Wild type p16INK4A is able to form a complex with either CDK4 or CDK6 and prevent formation of catalytically active CDK complexes consisting of CDK4 or CDK6 and D-type cyclins (CCND). Thus, p16INK4A prevents hyperphosphorylation of RB-family proteins, required for initiation of DNA replication in RB1-competent cells. Expression of p16INK4A increases in response to oxidative stress, leading to cellular senescence (programmed cell cycle arrest) under conditions of prolonged oxidative stress. Loss-of-function of p16INK4A frequently occurs in cancer, usually through loss of p16INK4A protein expression due to promoter hypermethylation or CDKN2A gene deletion (Merlo et al. 1995, Herman et al. 1995, Gonzalez-Zulueta et al. 1995, Wong et al. 1997, Witkiewicz et al. 2011, Shima et al. 2011, Tamayo-Orrego et al. 2016). Missense, nonsense and frameshift mutations in the CDKN2A locus can also impair p16INK4A function through expression of non-functional substitution mutants or truncated proteins (Kamb et al. 1994, Bartsch et al. 1995, Castellano et al. 1997). Germline intronic CDKN2A mutations that create aberrant splicing sites and result in expression of non-functional splicing variants of p16INK4A have been reported in familial melanoma (Harland et al. 2001, Harland et al. 2005). A CDKN2A gene mutation in the region encoding the 5'UTR of p16INK4A, reported in familial melanoma, creates a novel translation start codon and diminishes translation from the wild type start codon (Liu et al. 1999). However, mutations in the non coding regions of the CDKN2A gene are rare (Pollock et al. 2001).
p16INK4A defects enable cancerous cells to evade cell cycle arrest and senescence under prolonged oxidative stress (Tanaka et al. 1999, Chen 2000, Chen et al. 2004, Vurusaner et al. 2012, Rayess et al. 2012, LaPak and Burd 2014, Sharpless and Sherr 2015, Zhang et al. 2017). A cell cycle-independent role of p16INK4A in regulation of intracellular oxidative stress has been reported (Jenkins et al. 2011, Vurusaner et al. 2012, Jenkins et al. 2013).
Genomic deletions in the CDKN2A locus affect p14ARF, unless they are limited to exon 1alpha. The p14ARF promoter can also be hypermethylated in cancer, leading to loss of p14ARF expression. Some missense mutations occurring in exon 2 of the CDKN2A gene affect the p14ARF protein sequence. However, p14ARF mutants usually appear to be less functionally compromised than their p16INK4A counterparts. Most functional tests on p14ARF mutants examine the effect of mutations on MDM2 binding and TP53-mediated transcription of CDKN1A (p21), as well as sub-nuclear localization of p14ARF (Zhang and Xiong 1999, Schmitt et al. 1999, Eischen et al. 1999, Pinyol et al. 2000, Bostrom et al. 2001, Laud et al. 2006). Still, there are poorly explored functions of p14ARF that may be significantly affected in mutant p14ARF proteins detected in cancer (Itahana and Zhang 2008, Dominguez-Brauer et al. 2010).

Literature References
PubMed ID Title Journal Year
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Tanaka, T, Iwasa, Y, Kondo, S, Hiai, H, Toyokuni, S

Oncogene 1999
24136988 The molecular balancing act of p16(INK4a) in cancer and aging

LaPak, KM, Burd, CE

Mol. Cancer Res. 2014
26105537 Forging a signature of in vivo senescence

Sharpless, NE, Sherr, CJ

Nat. Rev. Cancer 2015
8589035 Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas

Bartsch, D, Shevlin, DW, Tung, WS, Kisker, O, Wells, SA, Goodfellow, PJ

Genes Chromosomes Cancer 1995
18538737 Mitochondrial p32 is a critical mediator of ARF-induced apoptosis

Itahana, K, Zhang, Y

Cancer Cell 2008
27846439 A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1-/- mice is correlated to increased cellular senescence

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Redox Biol 2017
26997276 Evasion of Cell Senescence Leads to Medulloblastoma Progression

Tamayo-Orrego, L, Wu, CL, Bouchard, N, Khedher, A, Swikert, SM, Remke, M, Skowron, P, Taylor, MD, Charron, F

Cell Rep 2016
9916806 Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma

Liu, L, Dilworth, D, Gao, L, Monzon, J, Summers, A, Lassam, N, Hogg, D

Nat. Genet. 1999
10498896 Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information

Ruas, M, Brookes, S, McDonald, NQ, Peters, G

Oncogene 1999
10854221 INK4a/ARF locus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene

Pinyol, M, Hernández, L, Martínez, A, Cobo, F, Hernández, S, Beà, S, López-Guillermo, A, Nayach, I, Palacín, A, Nadal, A, Fernández, PL, Montserrat, E, Cardesa, A, Campo, E

Am. J. Pathol. 2000
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Chen, QM

Ann. N. Y. Acad. Sci. 2000
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Eischen, CM, Weber, JD, Roussel, MF, Sherr, CJ, Cleveland, JL

Genes Dev. 1999
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Shima, K, Nosho, K, Baba, Y, Cantor, M, Meyerhardt, JA, Giovannucci, EL, Fuchs, CS, Ogino, S

Int. J. Cancer 2011
8153634 A cell cycle regulator potentially involved in genesis of many tumor types

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Science 1994
10360174 Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53

Zhang, Y, Xiong, Y

Mol. Cell 1999
15937071 Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma

Laud, K, Marian, C, Avril, MF, Barrois, M, Chompret, A, Goldstein, AM, Tucker, MA, Clark, PA, Peters, G, Chaudru, V, Demenais, F, Spatz, A, Smith, MW, Lenoir, GM, Bressac-de Paillerets, B

J. Med. Genet. 2006
11485924 Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas

Boström, J, Meyer-Puttlitz, B, Wolter, M, Blaschke, B, Weber, RG, Lichter, P, Ichimura, K, Collins, VP, Reifenberger, G

Am. J. Pathol. 2001
10541553 INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53

Schmitt, CA, McCurrach, ME, de Stanchina, E, Wallace-Brodeur, RR, Lowe, SW

Genes Dev. 1999
7553622 Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing

Gonzalez-Zulueta, M, Bender, CM, Yang, AS, Nguyen, T, Beart, RW, Van Tornout, JM, Jones, PA

Cancer Res. 1995
22019631 Tumor suppressor genes and ROS: complex networks of interactions

Vurusaner, B, Poli, G, Basaga, H

Free Radic. Biol. Med. 2012
11726555 A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees

Harland, M, Mistry, S, Bishop, DT, Bishop, JA

Hum. Mol. Genet. 2001
20838381 The p16(INK4A) tumor suppressor regulates cellular oxidative stress

Jenkins, NC, Liu, T, Cassidy, P, Leachman, SA, Boucher, KM, Goodson, AG, Samadashwily, G, Grossman, D

Oncogene 2011
9354451 CDKN2A/p16 is inactivated in most melanoma cell lines

Castellano, M, Pollock, PM, Walters, MK, Sparrow, LE, Down, LM, Gabrielli, BG, Parsons, PG, Hayward, NK

Cancer Res. 1997
7553621 Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers

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Cancer Res. 1995
11477665 Mutation analysis of the CDKN2A promoter in Australian melanoma families

Pollock, PM, Stark, MS, Palmer, JM, Walters, MK, Aitken, JF, Martin, NG, Hayward, NK

Genes Chromosomes Cancer 2001
9205067 p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas

Wong, DJ, Barrett, MT, Stöger, R, Emond, MJ, Reid, BJ

Cancer Res. 1997
15377661 Loss of proliferative capacity and induction of senescence in oxidatively stressed human fibroblasts

Chen, JH, Stoeber, K, Kingsbury, S, Ozanne, SE, Williams, GH, Hales, CN

J. Biol. Chem. 2004
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Jenkins, NC, Jung, J, Liu, T, Wilde, M, Holmen, SL, Grossman, D

J. Invest. Dermatol. 2013
20016279 Tumor suppression by ARF: gatekeeper and caretaker

Dominguez-Brauer, C, Brauer, PM, Chen, YJ, Pimkina, J, Raychaudhuri, P

Cell Cycle 2010
7585152 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers

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Nat. Med. 1995
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Genes Chromosomes Cancer 2005
21775818 The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments

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Cell Cycle 2011
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cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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