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Cell Cycle Checkpoints and Senescence

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Cellular Ageing and Replicative Senescence

Part of the book series: Healthy Ageing and Longevity ((HAL))

Abstract

Cellular senescence, an outcome of finite proliferative, limited repair and defence capacity of normal cells, is a widely accepted in vitro model for ageing studies. In a sharp contrast to cancer cells, it is firmly regulated by cell cycle checkpoints that ensure evasion of stressed and genetically modified cells, limiting their expansion and serve as an innate check to carcinogenesis. Tumour suppressors and their regulatory proteins play key roles, both as molecular sensors and regulators in this process. Aim of the present chapter is to sketch a brief understanding on how cellular senescence is regulated by major tumour suppressor and cell cycle checkpoint proteins as well as by some emerging molecules.

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References

  • Aggarwal BB, Totpal K, LaPushin R, Chaturvedi MM, Pereira-Smith OM, Smith JR (1995) Diminished responsiveness of senescent normal human fibroblasts to TNF-dependent proliferation and interleukin production is not due to its effect on the receptors or on the activation of a nuclear factor NF-kappa B. Exp Cell Res 218:381–388

    Article  CAS  PubMed  Google Scholar 

  • Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC (1996) Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A 93:13742–13747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ale-Agha N, Dyballa-Rukes N, Jakob S, Altschmied J, Haendeler J (2014) Cellular functions of the dual-targeted catalytic subunit of telomerase, telomerase reverse transcriptase–potential role in senescence and aging. Exp Gerontol 56:189–193

    Article  CAS  PubMed  Google Scholar 

  • Appella E (2001) Modulation of p53 function in cellular regulation. Eur J Biochem 268:2763

    Article  CAS  PubMed  Google Scholar 

  • Appella E, Anderson CW (2001) Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 268:2764–2772

    Article  CAS  PubMed  Google Scholar 

  • Atadja P, Wong H, Garkavtsev I, Veillette C, Riabowol K (1995) Increased activity of p53 in senescing fibroblasts. Proc Natl Acad Sci U S A 92:8348–8352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bandyopadhyay D, Gatza C, Donehower LA, Medrano EE (2005) Analysis of cellular senescence in culture in vivo: the senescence-associated beta-galactosidase assay. Curr Protoc Cell Biol 27:18.9:18.9.1–18.9.9

    Google Scholar 

  • Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y et al (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281:1674–1677

    Article  CAS  PubMed  Google Scholar 

  • Benevolenskaya EV, Frolov MV (2015) Emerging links between E2F control and mitochondrial function. Cancer Res 75:619–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blagosklonny MV (2002) p53: an ubiquitous target of anticancer drugs. Int J Cancer 98:161–166

    Article  CAS  PubMed  Google Scholar 

  • Blake MJ, Fargnoli J, Gershon D, Holbrook NJ (1991) Concomitant decline in heat-induced hyperthermia and HSP70 mRNA expression in aged rats. Am J Physiol 260:R663–R667

    CAS  PubMed  Google Scholar 

  • Bond JA, Wyllie FS, Wynford-Thomas D (1994) Escape from senescence in human diploid fibroblasts induced directly by mutant p53. Oncogene 9:1885–1889

    CAS  PubMed  Google Scholar 

  • Bond J, Haughton M, Blaydes J, Gire V, Wynford-Thomas D, Wyllie F (1996) Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence. Oncogene 13:2097–2104

    CAS  PubMed  Google Scholar 

  • Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dorken B, Jenuwein T, Schmitt CA (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436:660–665

    Article  CAS  PubMed  Google Scholar 

  • Brenner AJ, Stampfer MR, Aldaz CM (1998) Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene 17:199–205

    Article  CAS  PubMed  Google Scholar 

  • Broustas CG, Lieberman HB (2014) DNA damage response genes and the development of cancer metastasis. Radiat Res 181:111–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown JP, Wei W, Sedivy JM (1997) Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277:831–834

    Article  CAS  PubMed  Google Scholar 

  • Burhans WC, Heintz NH (2009) The cell cycle is a redox cycle: linking phase-specific targets to cell fate. Free Radic Biol Med 47:1282–1293

    Article  CAS  PubMed  Google Scholar 

  • Campisi J (2000) Cancer, aging and cellular senescence. In Vivo 14:183–188

    CAS  PubMed  Google Scholar 

  • Campisi J (2002) Cancer and aging: yin, yang, and p53. Sci Aging Knowl Environ 2002:pe1

    Article  Google Scholar 

  • Campisi J (2005a) Aging, tumor suppression and cancer: high wire-act! Mech Ageing Dev 126:51–58

    Article  CAS  PubMed  Google Scholar 

  • Campisi J (2005b) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522

    Article  CAS  PubMed  Google Scholar 

  • Campisi J (2008) Aging and cancer cell biology, 2008. Aging Cell 7:281–284

    Article  CAS  PubMed  Google Scholar 

  • Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campisi J, Robert L (2014) Cell senescence: role in aging and age-related diseases. Interdiscip Top Gerontol 39:45–61

    Article  PubMed  PubMed Central  Google Scholar 

  • Canman CE, Lim DS (1998) The role of ATM in DNA damage responses and cancer. Oncogene 17:3301–3308

    Article  PubMed  Google Scholar 

  • Carnero A (2013) Markers of cellular senescence. Methods Mol Biol 965:63–81

    Article  CAS  PubMed  Google Scholar 

  • Chehab NH, Malikzay A, Stavridi ES, Halazonetis TD (1999) Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc Natl Acad Sci U S A 96:13777–13782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen QM (2000) Replicative senescence and oxidant-induced premature senescence. Beyond the control of cell cycle checkpoints. Ann N Y Acad Sci 908:111–125

    Article  CAS  PubMed  Google Scholar 

  • Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN (1995) Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A 92:4337–4341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen QM, Bartholomew JC, Campisi J, Acosta M, Reagan JD, Ames BN (1998) Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J 332:43–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W et al (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung CT, Kaul SC, Wadhwa R (2010) Molecular bridging of aging and cancer: a CARF link. Ann N Y Acad Sci 1197:129–133

    Article  CAS  PubMed  Google Scholar 

  • Cheung CT, Singh R, Yoon AR, Hasan MK, Yaguchi T, Kaul SC, Yun CO, Wadhwa R (2011) Molecular characterization of apoptosis induced by CARF silencing in human cancer cells. Cell Death Differ 18:589–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung CT, Singh R, Kalra RS, Kaul SC, Wadhwa R (2014) Collaborator of ARF (CARF) regulates proliferative fate of human cells by dose-dependent regulation of DNA damage signaling. J Biol Chem 289:18258–18269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT, Park SC (2003) Senescent phenotype can be reversed by reduction of caveolin status. J Biol Chem 278:27789–27795

    Article  CAS  PubMed  Google Scholar 

  • Cho KA, Ryu SJ, Oh YS, Park JH, Lee JW, Kim HP, Kim KT, Jang IS, Park SC (2004) Morphological adjustment of senescent cells by modulating caveolin-1 status. J Biol Chem 279:42270–42278

    Article  CAS  PubMed  Google Scholar 

  • Chun SG, Shaeffer DS, Bryant-Greenwood PK (2011) The Werner’s syndrome RecQ helicase/exonuclease at the nexus of cancer and aging. Hawaii Med J 70:52–55

    PubMed  PubMed Central  Google Scholar 

  • Cipressa F, Cenci G (2013) DNA damage response, checkpoint activation and dysfunctional telomeres: face to face between mammalian cells and drosophila. Tsitologiia 55:211–217

    CAS  PubMed  Google Scholar 

  • Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233

    Article  CAS  PubMed  Google Scholar 

  • Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski K (2006) A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10:459–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cristofalo VJ, Sharf BB (1973) Cellular senescence and DNA synthesis. Thymidine incorporation as a measure of population age in human diploid cells. Exp Cell Res 76:419–427

    Article  CAS  PubMed  Google Scholar 

  • Cristofalo VJ, Volker C, Francis MK, Tresini M (1998) Age-dependent modifications of gene expression in human fibroblasts. Crit Rev Eukaryot Gene Expr 8:43–80

    Article  CAS  PubMed  Google Scholar 

  • d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198

    Article  PubMed  CAS  Google Scholar 

  • Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M (2007) A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev 21:379–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demaria M, Desprez PY, Campisi J, Velarde MC (2015) Cell autonomous and non-autonomous effects of senescent cells in the skin. J Invest Dermatol. doi:10.1038/jid.2015.108, Epub ahead of print

    PubMed  PubMed Central  Google Scholar 

  • Deocaris CC, Widodo N, Shrestha BG, Kaur K, Ohtaka M, Yamasaki K, Kaul SC, Wadhwa R (2007) Mortalin sensitizes human cancer cells to MKT-077-induced senescence. Cancer Lett 252:259–269

    Article  CAS  PubMed  Google Scholar 

  • Deocaris CC, Lu WJ, Kaul SC, Wadhwa R (2013) Druggability of mortalin for cancer and neuro-degenerative disorders. Curr Pharm Des 19:418–429

    Article  CAS  PubMed  Google Scholar 

  • Di Leonardo A, Linke SP, Clarkin K, Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 8:2540–2551

    Article  PubMed  Google Scholar 

  • Dimri GP, Campisi J (1994) Molecular and cell biology of replicative senescence. Cold Spring Harb Symp Quant Biol 59:67–73

    Article  CAS  PubMed  Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221

    Article  CAS  PubMed  Google Scholar 

  • Dulic V, Kaufmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, Elledge SJ, Reed SI (1994) p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76:1013–1023

    Article  CAS  PubMed  Google Scholar 

  • Duncan EL, Reddel RR (1997) Genetic changes associated with immortalization. A review. Biochemistry (Mosc) 62:1263–1274

    CAS  Google Scholar 

  • Dyson N (1994) pRB, p107 and the regulation of the E2F transcription factor. J Cell Sci Suppl 18:81–87

    Article  CAS  PubMed  Google Scholar 

  • el-Deiry WS (1998) Regulation of p53 downstream genes. Semin Cancer Biol 8:345–357

    Article  CAS  PubMed  Google Scholar 

  • Elias J, Dimitrio L, Clairambault J, Natalini R (2014) The p53 protein and its molecular network: modelling a missing link between DNA damage and cell fate. Biochim Biophys Acta 1844:232–247

    Article  CAS  PubMed  Google Scholar 

  • Falandry C, Gilson E, Rudolph KL (2013) Are aging biomarkers clinically relevant in oncogeriatrics? Crit Rev Oncol Hematol 85:257–265

    Article  PubMed  Google Scholar 

  • Fang L, Igarashi M, Leung J, Sugrue MM, Lee SW, Aaronson SA (1999) p21Waf1/Cip1/Sdi1 induces permanent growth arrest with markers of replicative senescence in human tumor cells lacking functional p53. Oncogene 18:2789–2797

    Article  CAS  PubMed  Google Scholar 

  • Fargnoli J, Kunisada T, Fornace AJ Jr, Schneider EL, Holbrook NJ (1990) Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats. Proc Natl Acad Sci U S A 87:846–850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng R, He W, Ochi H (2001) A new murine oxidative stress model associated with senescence. Mech Ageing Dev 122:547–559

    Article  CAS  PubMed  Google Scholar 

  • Futreal PA, Barrett JC (1991) Failure of senescent cells to phosphorylate the RB protein. Oncogene 6:1109–1113

    CAS  PubMed  Google Scholar 

  • Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM, Weill JC, Blasco MA, Serrano M (2002) “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 21:6225–6235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gelvan D, Moreno V, Clopton DA, Chen Q, Saltman P (1995) Sites and mechanisms of low-level oxidative stress in cultured cells. Biochem Biophys Res Commun 206:421–428

    Article  CAS  PubMed  Google Scholar 

  • Gerland LM, Peyrol S, Lallemand C, Branche R, Magaud JP, Ffrench M (2003) Association of increased autophagic inclusions labeled for beta-galactosidase with fibroblastic aging. Exp Gerontol 38:887–895

    Article  CAS  PubMed  Google Scholar 

  • Girardi AJ, Jensen FC, Koprowski H (1965) Sv40-induced tranformation of human diploid cells: crisis and recovery. J Cell Physiol 65:69–83

    Article  CAS  PubMed  Google Scholar 

  • Gire V (2005) Senescence: a telomeric limit to immortality or a cellular response to physiologic stresses? Med Sci (Paris) 21:491–497

    Article  Google Scholar 

  • Gire V, Wynford-Thomas D (1998) Reinitiation of DNA synthesis and cell division in senescent human fibroblasts by microinjection of anti-p53 antibodies. Mol Cell Biol 18:1611–1621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldstein S (1990) Replicative senescence: the human fibroblast comes of age. Science 249:1129–1133

    Article  CAS  PubMed  Google Scholar 

  • Goligorsky MS, Chen J, Patschan S (2009) Stress-induced premature senescence of endothelial cells: a perilous state between recovery and point of no return. Curr Opin Hematol 16:215–219

    Article  CAS  PubMed  Google Scholar 

  • Gonos ES, Derventzi A, Kveiborg M, Agiostratidou G, Kassem M, Clark BF, Jat PS, Rattan SI (1998) Cloning and identification of genes that associate with mammalian replicative senescence. Exp Cell Res 240:66–74

    Article  CAS  PubMed  Google Scholar 

  • Grover A, Priyandoko D, Gao R, Shandilya A, Widodo N, Bisaria VS, Kaul SC, Wadhwa R, Sundar D (2012) Withanone binds to mortalin and abrogates mortalin-p53 complex: computational and experimental evidence. Int J Biochem Cell Biol 44:496–504

    Article  CAS  PubMed  Google Scholar 

  • Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319:1352–1355

    Article  CAS  PubMed  Google Scholar 

  • Halvorsen TL, Beattie GM, Lopez AD, Hayek A, Levine F (2000) Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro. J Endocrinol 166:103–109

    Article  CAS  PubMed  Google Scholar 

  • Hara E, Tsurui H, Shinozaki A, Nakada S, Oda K (1991) Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1. Biochem Biophys Res Commun 179:528–534

    Article  CAS  PubMed  Google Scholar 

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805–816

    Article  CAS  PubMed  Google Scholar 

  • Hasan MK, Yaguchi T, Sugihara T, Kumar PK, Taira K, Reddel RR, Kaul SC, Wadhwa R (2002) CARF is a novel protein that cooperates with mouse p19ARF (human p14ARF) in activating p53. J Biol Chem 277:37765–37770

    Article  CAS  PubMed  Google Scholar 

  • Hasan MK, Yaguchi T, Minoda Y, Hirano T, Taira K, Wadhwa R, Kaul SC (2004) Alternative reading frame protein (ARF)-independent function of CARF (collaborator of ARF) involves its interactions with p53: evidence for a novel p53-activation pathway and its negative feedback control. Biochem J 380:605–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hasan MK, Yaguchi T, Harada JI, Hirano T, Wadhwa R, Kaul SC (2008) CARF (collaborator of ARF) interacts with HDM2: evidence for a novel regulatory feedback regulation of CARF-p53-HDM2-p21WAF1 pathway. Int J Oncol 32:663–671

    CAS  PubMed  Google Scholar 

  • Hayflick L (2007) Biological aging is no longer an unsolved problem. Ann N Y Acad Sci 1100:1–13

    Article  CAS  PubMed  Google Scholar 

  • Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621

    Article  CAS  PubMed  Google Scholar 

  • Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14:501–513

    Article  CAS  PubMed  Google Scholar 

  • Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW (2000) DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287:1824–1827

    Article  CAS  PubMed  Google Scholar 

  • Holliday R (1990) The limited proliferation of cultured human diploid cells: regulation or senescence? J Gerontol 45:B36–B41

    Article  CAS  PubMed  Google Scholar 

  • Horikoshi T, Balin AK, Carter DM (1986) Effect of oxygen on the growth of human epidermal keratinocytes. J Invest Dermatol 86:424–427

    Article  CAS  PubMed  Google Scholar 

  • Horn HF, Vousden KH (2007) Coping with stress: multiple ways to activate p53. Oncogene 26:1306–1316

    Article  CAS  PubMed  Google Scholar 

  • Huschtscha LI, Holliday R (1983) Limited and unlimited growth of SV40-transformed cells from human diploid MRC-5 fibroblasts. J Cell Sci 63:77–99

    CAS  PubMed  Google Scholar 

  • Huschtscha LI, Reddel RR (1999) p16(INK4a) and the control of cellular proliferative life span. Carcinogenesis 20:921–926

    Article  CAS  PubMed  Google Scholar 

  • Huschtscha LI, Noble JR, Neumann AA, Moy EL, Barry P, Melki JR, Clark SJ, Reddel RR (1998) Loss of p16INK4 expression by methylation is associated with lifespan extension of human mammary epithelial cells. Cancer Res 58:3508–3512

    CAS  PubMed  Google Scholar 

  • Indran IR, Hande MP, Pervaiz S (2010) Tumor cell redox state and mitochondria at the center of the non-canonical activity of telomerase reverse transcriptase. Mol Aspects Med 31:21–28

    Article  CAS  PubMed  Google Scholar 

  • Jarrard DF, Sarkar S, Shi Y, Yeager TR, Magrane G, Kinoshita H, Nassif N, Meisner L, Newton MA, Waldman FM et al (1999) p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells. Cancer Res 59:2957–2964

    CAS  PubMed  Google Scholar 

  • Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U (2007) Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev 128:36–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91:649–659

    Article  CAS  PubMed  Google Scholar 

  • Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ (1998) Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 95:8292–8297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanai M, Ma Z, Izumi H, Kim SH, Mattison CP, Winey M, Fukasawa K (2007) Physical and functional interaction between mortalin and Mps1 kinase. Genes Cells Devoted Mol Cell Mech 12:797–810

    CAS  Google Scholar 

  • Karayan L, Riou JF, Seite P, Migeon J, Cantereau A, Larsen CJ (2001) Human ARF protein interacts with topoisomerase I and stimulates its activity. Oncogene 20:836–848

    Article  CAS  PubMed  Google Scholar 

  • Kato D, Miyazawa K, Ruas M, Starborg M, Wada I, Oka T, Sakai T, Peters G, Hara E (1998) Features of replicative senescence induced by direct addition of antennapedia-p16INK4A fusion protein to human diploid fibroblasts. FEBS Lett 427:203–208

    Article  CAS  PubMed  Google Scholar 

  • Kaul SC, Reddel RR, Mitsui Y, Wadhwa R (2001) An N-terminal region of mot-2 binds to p53 in vitro. Neoplasia 3:110–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaul SC, Aida S, Yaguchi T, Kaur K, Wadhwa R (2005) Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides. J Biol Chem 280:39373–39379

    Article  CAS  PubMed  Google Scholar 

  • Kaul Z, Cesare AJ, Huschtscha LI, Neumann AA, Reddel RR (2012) Five dysfunctional telomeres predict onset of senescence in human cells. EMBO Rep 13:52–59

    Article  CAS  PubMed Central  Google Scholar 

  • Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127:265–275

    Article  CAS  PubMed  Google Scholar 

  • Kirkwood TB (2008) Understanding ageing from an evolutionary perspective. J Intern Med 263:117–127

    Article  CAS  PubMed  Google Scholar 

  • Klement K, Goodarzi AA (2014) DNA double strand break responses and chromatin alterations within the aging cell. Exp Cell Res 329:42–52

    Article  CAS  PubMed  Google Scholar 

  • Knippschild U, Milne D, Campbell L, Meek D (1996) p53 N-terminus-targeted protein kinase activity is stimulated in response to wild type p53 and DNA damage. Oncogene 13:1387–1393

    CAS  PubMed  Google Scholar 

  • Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–1307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krtolica A, Campisi J (2002) Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int J Biochem Cell Biol 34:1401–1414

    Article  CAS  PubMed  Google Scholar 

  • Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A 98:12072–12077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kulju KS, Lehman JM (1995) Increased p53 protein associated with aging in human diploid fibroblasts. Exp Cell Res 217:336–345

    Article  CAS  PubMed  Google Scholar 

  • Kumazaki T, Robetorye RS, Robetorye SC, Smith JR (1991) Fibronectin expression increases during in vitro cellular senescence: correlation with increased cell area. Exp Cell Res 195:13–19

    Article  CAS  PubMed  Google Scholar 

  • Kurz DJ, Decary S, Hong Y, Erusalimsky JD (2000) Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 113:3613–3622

    CAS  PubMed  Google Scholar 

  • Lavigueur A, Maltby V, Mock D, Rossant J, Pawson T, Bernstein A (1989) High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9:3982–3991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee M, Lee JS (2014) Exploiting tumor cell senescence in anticancer therapy. BMB Rep 47:51–59

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee AC, Fenster BE, Ito H, Takeda K, Bae NS, Hirai T, Yu ZX, Ferrans VJ, Howard BH, Finkel T (1999) Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem 274:7936–7940

    Article  CAS  PubMed  Google Scholar 

  • Liao JM, Cao B, Zhou X, Lu H (2014) New insights into p53 functions through its target microRNAs. J Mol Cell Biol 6:206–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 12:3008–3019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu B, Chen Y, St Clair DK (2008) ROS and p53: a versatile partnership. Free Radic Biol Med 44:1529–1535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Zhang C, Feng Z (2014) Tumor suppressor p53 and its gain-of-function mutants in cancer. Acta Biochim Biophys Sin (Shanghai) 46:170–179

    Article  CAS  Google Scholar 

  • Liu J, Zhang C, Hu W, Feng Z (2015) Tumor suppressor p53 and its mutants in cancer metabolism. Cancer Lett 356:197–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu WJ, Lee NP, Kaul SC, Lan F, Poon RT, Wadhwa R, Luk JM (2011a) Induction of mutant p53-dependent apoptosis in human hepatocellular carcinoma by targeting stress protein mortalin. Int J Cancer 129:1806–1814

    Article  CAS  PubMed  Google Scholar 

  • Lu WJ, Lee NP, Kaul SC, Lan F, Poon RT, Wadhwa R, Luk JM (2011b) Mortalin-p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy. Cell Death Differ 18:1046–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ludlow JW, DeCaprio JA, Huang CM, Lee WH, Paucha E, Livingston DM (1989) SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family. Cell 56:57–65

    Article  CAS  PubMed  Google Scholar 

  • Ma W, Wlaschek M, Hommel C, Schneider LA, Scharffetter-Kochanek K (2002) Psoralen plus UVA (PUVA) induced premature senescence as a model for stress-induced premature senescence. Exp Gerontol 37:1197–1201

    Article  CAS  PubMed  Google Scholar 

  • Ma Z, Izumi H, Kanai M, Kabuyama Y, Ahn NG, Fukasawa K (2006) Mortalin controls centrosome duplication via modulating centrosomal localization of p53. Oncogene 25:5377–5390

    Article  CAS  PubMed  Google Scholar 

  • Maccormick RE (2006) Possible acceleration of aging by adjuvant chemotherapy: a cause of early onset frailty? Med Hypotheses 67:212–215

    Article  CAS  PubMed  Google Scholar 

  • Mackenzie NC, MacRae VE (2011) The role of cellular senescence during vascular calcification: a key paradigm in aging research. Curr Aging Sci 4:128–136

    Article  CAS  PubMed  Google Scholar 

  • Maclean K, Rogan EM, Whitaker NJ, Chang AC, Rowe PB, Dalla-Pozza L, Symonds G, Reddel RR (1994) In vitro transformation of Li-Fraumeni syndrome fibroblasts by SV40 large T antigen mutants. Oncogene 9:719–725

    CAS  PubMed  Google Scholar 

  • Maier AB, Westendorp RG (2009) Relation between replicative senescence of human fibroblasts and life history characteristics. Ageing Res Rev 8:237–243

    Article  CAS  PubMed  Google Scholar 

  • Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H (2004) Modulation of mammalian life span by the short isoform of p53. Genes Dev 18:306–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcotte R, Wang E (2002) Replicative senescence revisited. J Gerontol A Biol Sci Med Sci 57:B257–B269

    Article  PubMed  Google Scholar 

  • Martelli F, Hamilton T, Silver DP, Sharpless NE, Bardeesy N, Rokas M, DePinho RA, Livingston DM, Grossman SR (2001) p19ARF targets certain E2F species for degradation. Proc Natl Acad Sci U S A 98:4455–4460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martien S, Abbadie C (2007) Acquisition of oxidative DNA damage during senescence: the first step toward carcinogenesis? Ann N Y Acad Sci 1119:51–63

    Article  CAS  PubMed  Google Scholar 

  • Matheu A, Pantoja C, Efeyan A, Criado LM, Martin-Caballero J, Flores JM, Klatt P, Serrano M (2004) Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging. Genes Dev 18:2736–2746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA, Serrano M (2007) Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448:375–379

    Article  CAS  PubMed  Google Scholar 

  • McConnell BB, Starborg M, Brookes S, Peters G (1998) Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts. Curr Biol 8:351–354

    Article  CAS  PubMed  Google Scholar 

  • Medcalf AS, Klein-Szanto AJ, Cristofalo VJ (1996) Expression of p21 is not required for senescence of human fibroblasts. Cancer Res 56:4582–4585

    CAS  PubMed  Google Scholar 

  • Meinardi MT, Gietema JA, van Veldhuisen DJ, van der Graaf WT, de Vries EG, Sleijfer DT (2000) Long-term chemotherapy-related cardiovascular morbidity. Cancer Treat Rev 26:429–447

    Article  CAS  PubMed  Google Scholar 

  • Menendez S, Khan Z, Coomber DW, Lane DP, Higgins M, Koufali MM, Lain S (2003) Oligomerization of the human ARF tumor suppressor and its response to oxidative stress. J Biol Chem 278:18720–18729

    Article  CAS  PubMed  Google Scholar 

  • Mengual Gomez DL, Armando RG, Farina HG, Gomez DE (2014) Telomerase and telomere: their structure and dynamics in health and disease. Medicina (B Aires) 74:69–76

    Google Scholar 

  • Menon V, Povirk L (2014) Involvement of p53 in the repair of DNA double strand breaks: multifaceted roles of p53 in homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Subcell Biochem 85:321–336

    Article  PubMed  PubMed Central  Google Scholar 

  • Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720–724

    Article  CAS  PubMed  Google Scholar 

  • Mirzayans R, Andrais B, Scott A, Murray D (2012) New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy. J Biomed Biotechnol 2012:170325

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mitsui Y, Schneider EL (1976) Increased nuclear sizes in senescent human diploid fibroblast cultures. Exp Cell Res 100:147–152

    Article  CAS  PubMed  Google Scholar 

  • Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore PS, Beghelli S, Zamboni G, Scarpa A (2003) Genetic abnormalities in pancreatic cancer. Mol Cancer 2:7

    Article  PubMed  PubMed Central  Google Scholar 

  • Musilova K, Mraz M (2015) MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. Leukemia 29:1004–1017

    Article  CAS  PubMed  Google Scholar 

  • Nevins JR (1992) E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science 258:424–429

    Article  CAS  PubMed  Google Scholar 

  • Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR (1994) Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 211:90–98

    Article  CAS  PubMed  Google Scholar 

  • Pantoja C, Serrano M (1999) Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras. Oncogene 18:4974–4982

    Article  CAS  PubMed  Google Scholar 

  • Papazoglu C, Mills AA (2007) p53: at the crossroad between cancer and ageing. J Pathol 211:124–133

    Article  CAS  PubMed  Google Scholar 

  • Passos JF, Von Zglinicki T (2006) Oxygen free radicals in cell senescence: are they signal transducers? Free Radic Res 40:1277–1283

    Article  CAS  PubMed  Google Scholar 

  • Passos JF, von Zglinicki T, Saretzki G (2006) Mitochondrial dysfunction and cell senescence: cause or consequence? Rejuvenation Res 9:64–68

    Article  CAS  PubMed  Google Scholar 

  • Passos JF, Saretzki G, von Zglinicki T (2007) DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res 35:7505–7513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pauklin S, Kristjuhan A, Maimets T, Jaks V (2005) ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress. Biochem Biophys Res Commun 334:386–394

    Article  CAS  PubMed  Google Scholar 

  • Penna E, Orso F, Taverna D (2015) miR-214 as a key hub that controls cancer networks: small player, multiple functions. J Invest Dermatol 135:960–969

    Article  CAS  PubMed  Google Scholar 

  • Pereira-Smith OM, Smith JR (1983) Evidence for the recessive nature of cellular immortality. Science 221:964–966

    Article  CAS  PubMed  Google Scholar 

  • Pignolo RJ, Martin BG, Horton JH, Kalbach AN, Cristofalo VJ (1998) The pathway of cell senescence: WI-38 cells arrest in late G1 and are unable to traverse the cell cycle from a true G0 state. Exp Gerontol 33:67–80

    Article  CAS  PubMed  Google Scholar 

  • Prieur A, Peeper DS (2008) Cellular senescence in vivo: a barrier to tumorigenesis. Curr Opin Cell Biol 20:150–155

    Article  CAS  PubMed  Google Scholar 

  • Przybylska D, Mosieniak G (2014) The role of NADPH oxidase NOX4 in regulation of proliferation, senescence and differentiation of the cells. Postepy Biochem 60:69–76

    CAS  PubMed  Google Scholar 

  • Qi Y, Gregory MA, Li Z, Brousal JP, West K, Hann SR (2004) p19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature 431:712–717

    Article  CAS  PubMed  Google Scholar 

  • Quelle DE, Zindy F, Ashmun RA, Sherr CJ (1995) Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83:993–1000

    Article  CAS  PubMed  Google Scholar 

  • Raghu TY, Venkatesulu GA, Kantharaj GR, Suresh T, Veeresh V, Hanumanthappa Y (2001) Progeria (Hutchison-Gilford syndrome) in siblings: in an autosomal recessive pattern of inheritance. Indian J Dermatol Venereol Leprol 67:261–262

    CAS  PubMed  Google Scholar 

  • Rattan SI (1996) Synthesis, modifications, and turnover of proteins during aging. Exp Gerontol 31:33–47

    Article  CAS  PubMed  Google Scholar 

  • Rayess H, Wang MB, Srivatsan ES (2012) Cellular senescence and tumor suppressor gene p16. Int J Cancer 130:1715–1725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reddel RR (1998) Genes involved in the control of cellular proliferative potential. Ann N Y Acad Sci 854:8–19

    Article  CAS  PubMed  Google Scholar 

  • Reznikoff CA, Yeager TR, Belair CD, Savelieva E, Puthenveettil JA, Stadler WM (1996) Elevated p16 at senescence and loss of p16 at immortalization in human papillomavirus 16 E6, but not E7, transformed human uroepithelial cells. Cancer Res 56:2886–2890

    CAS  PubMed  Google Scholar 

  • Rizos H, Diefenbach E, Badhwar P, Woodruff S, Becker TM, Rooney RJ, Kefford RF (2003) Association of p14ARF with the p120E4F transcriptional repressor enhances cell cycle inhibition. J Biol Chem 278:4981–4989

    Article  CAS  PubMed  Google Scholar 

  • Robbins E, Levine EM, Eagle H (1970) Morphologic changes accompanying senescence of cultured human diploid cells. J Exp Med 131:1211–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robles SJ, Adami GR (1998) Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene 16:1113–1123

    Article  CAS  PubMed  Google Scholar 

  • Rogan EM, Bryan TM, Hukku B, Maclean K, Chang AC, Moy EL, Englezou A, Warneford SG, Dalla-Pozza L, Reddel RR (1995) Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts. Mol Cell Biol 15:4745–4753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saretzki G, Feng J, von Zglinicki T, Villeponteau B (1998) Similar gene expression pattern in senescent and hyperoxic-treated fibroblasts. J Gerontol A Biol Sci Med Sci 53:B438–B442

    Article  CAS  PubMed  Google Scholar 

  • Sarkisian CJ, Keister BA, Stairs DB, Boxer RB, Moody SE, Chodosh LA (2007) Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol 9:493–505

    Article  CAS  PubMed  Google Scholar 

  • Satyanarayana A, Greenberg RA, Schaetzlein S, Buer J, Masutomi K, Hahn WC, Zimmermann S, Martens U, Manns MP, Rudolph KL (2004) Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol Cell Biol 24:5459–5474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serrano M, Blasco MA (2007) Cancer and ageing: convergent and divergent mechanisms. Nat Rev Mol Cell Biol 8:715–722

    Article  CAS  PubMed  Google Scholar 

  • Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA (1996) Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:27–37

    Article  CAS  PubMed  Google Scholar 

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602

    Article  CAS  PubMed  Google Scholar 

  • Sharpless NE (2004) Ink4a/Arf links senescence and aging. Exp Gerontol 39:1751–1759

    Article  CAS  PubMed  Google Scholar 

  • Sharpless NE, DePinho RA (2002) p53: good cop/bad cop. Cell 110:9–12

    Article  CAS  PubMed  Google Scholar 

  • Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413:86–91

    Article  CAS  PubMed  Google Scholar 

  • Shay JW, Roninson IB (2004) Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 23:2919–2933

    Article  CAS  PubMed  Google Scholar 

  • Shay JW, Wright WE (1989) Quantitation of the frequency of immortalization of normal human diploid fibroblasts by SV40 large T-antigen. Exp Cell Res 184:109–118

    Article  CAS  PubMed  Google Scholar 

  • Shay JW, Wright WE (2005) Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26:867–874

    Article  CAS  PubMed  Google Scholar 

  • Shay JW, Wright WE, Brasiskyte D, Van der Haegen BA (1993) E6 of human papillomavirus type 16 can overcome the M1 stage of immortalization in human mammary epithelial cells but not in human fibroblasts. Oncogene 8:1407–1413

    CAS  PubMed  Google Scholar 

  • Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14:289–300

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sikora E, Arendt T, Bennett M, Narita M (2011) Impact of cellular senescence signature on ageing research. Ageing Res Rev 10:146–152

    Article  CAS  PubMed  Google Scholar 

  • Smith JR, Pereira-Smith OM (1996) Replicative senescence: implications for in vivo aging and tumor suppression. Science 273:63–67

    Article  CAS  PubMed  Google Scholar 

  • Smith JR, Pereira-Smith OM, Braunschweiger KI, Roberts TW, Whitney RG (1980) A general method for determining the replicative age of normal animal cell cultures. Mech Ageing Dev 12:355–365

    Article  CAS  PubMed  Google Scholar 

  • Sperka T, Wang J, Rudolph KL (2012) DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol 13:579–590

    Article  CAS  PubMed  Google Scholar 

  • Stein GH, Dulic V (1995) Origins of G1 arrest in senescent human fibroblasts. Bioessays 17:537–543

    Article  CAS  PubMed  Google Scholar 

  • Stein GH, Beeson M, Gordon L (1990) Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249:666–669

    Article  CAS  PubMed  Google Scholar 

  • Stein GH, Drullinger LF, Soulard A, Dulic V (1999) Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol 19:2109–2117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH et al (1998) The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17:5001–5014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stracker TH, Roig I, Knobel PA, Marjanovic M (2013) The ATM signaling network in development and disease. Front Genet 4:37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sugihara T, Kaul SC, Kato J, Reddel RR, Nomura H, Wadhwa R (2001) Pex19p dampens the p19ARF-p53-p21WAF1 tumor suppressor pathway. J Biol Chem 276:18649–18652

    Article  CAS  PubMed  Google Scholar 

  • Suzuki M, Boothman DA (2008) Stress-induced premature senescence (SIPS) – influence of SIPS on radiotherapy. J Radiat Res (Tokyo) 49:105–112

    Article  Google Scholar 

  • Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123:966–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thweatt R, Goldstein S (1993) Werner syndrome and biological ageing: a molecular genetic hypothesis. Bioessays 15:421–426

    Article  CAS  PubMed  Google Scholar 

  • Tian H, Gao Z, Li H, Zhang B, Wang G, Zhang Q, Pei D, Zheng J (2015) DNA damage response – a double-edged sword in cancer prevention and cancer therapy. Cancer Lett 358:8–16

    Article  CAS  PubMed  Google Scholar 

  • Toussaint O, Medrano EE, von Zglinicki T (2000) Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Exp Gerontol 35:927–945

    Article  CAS  PubMed  Google Scholar 

  • Tresini M, Mawal-Dewan M, Cristofalo VJ, Sell C (1998) A phosphatidylinositol 3-kinase inhibitor induces a senescent-like growth arrest in human diploid fibroblasts. Cancer Res 58:1–4

    CAS  PubMed  Google Scholar 

  • Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C et al (2002) p53 mutant mice that display early ageing-associated phenotypes. Nature 415:45–53

    Article  CAS  PubMed  Google Scholar 

  • Vallejo AN, Weyand CM, Goronzy JJ (2004) T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection. Trends Mol Med 10:119–124

    Article  CAS  PubMed  Google Scholar 

  • Vargas J, Feltes BC, Poloni Jde F, Lenz G, Bonatto D (2012) Senescence; an endogenous anticancer mechanism. Front Biosci (Landmark Ed) 17:2616–2643

    Article  CAS  Google Scholar 

  • Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D, Harley CB (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 52:661–667

    CAS  PubMed  PubMed Central  Google Scholar 

  • Velarde MC, Demaria M, Campisi J (2013) Senescent cells and their secretory phenotype as targets for cancer therapy. Interdiscip Top Gerontol 38:17–27

    Article  PubMed  PubMed Central  Google Scholar 

  • Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445:661–665

    Article  CAS  PubMed  Google Scholar 

  • Vivo M, Calogero RA, Sansone F, Calabro V, Parisi T, Borrelli L, Saviozzi S, La Mantia G (2001) The human tumor suppressor arf interacts with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein. J Biol Chem 276:14161–14169

    CAS  PubMed  Google Scholar 

  • Vogt M, Haggblom C, Yeargin J, Christiansen-Weber T, Haas M (1998) Independent induction of senescence by p16INK4a and p21CIP1 in spontaneously immortalized human fibroblasts. Cell Growth Differ 9:139–146

    CAS  PubMed  Google Scholar 

  • von Zglinicki T, Saretzki G, Docke W, Lotze C (1995) Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp Cell Res 220:186–193

    Article  Google Scholar 

  • Vurusaner B, Poli G, Basaga H (2012) Tumor suppressor genes and ROS: complex networks of interactions. Free Radic Biol Med 52:7–18

    Article  CAS  PubMed  Google Scholar 

  • Wadhwa R, Kaul SC, Ikawa Y, Sugimoto Y (1991) Protein markers for cellular mortality and immortality. Mutat Res 256:243–254

    Article  CAS  PubMed  Google Scholar 

  • Wadhwa R, Kaul SC, Mitsui Y (1994) Cellular mortality to immortalization: mortalin. Cell Struct Funct 19:1–10

    Article  CAS  PubMed  Google Scholar 

  • Wadhwa R, Takano S, Robert M, Yoshida A, Nomura H, Reddel RR, Mitsui Y, Kaul SC (1998) Inactivation of tumor suppressor p53 by mot-2, a hsp70 family member. J Biol Chem 273:29586–29591

    Article  CAS  PubMed  Google Scholar 

  • Wadhwa R, Kaul SC, Mitsui Y (2000a) Cellular mortality and immortalization: a complex interplay of multiple gene functions. Prog Mol Subcell Biol 24:191–204

    Article  CAS  PubMed  Google Scholar 

  • Wadhwa R, Sugihara T, Yoshida A, Nomura H, Reddel RR, Simpson R, Maruta H, Kaul SC (2000b) Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Res 60:6818–6821

    CAS  PubMed  Google Scholar 

  • Wadhwa R, Colgin L, Yaguchi T, Taira K, Reddel RR, Kaul SC (2002a) Rhodacyanine dye MKT-077 inhibits in vitro telomerase assay but has no detectable effects on telomerase activity in vivo. Cancer Res 62:4434–4438

    CAS  PubMed  Google Scholar 

  • Wadhwa R, Sugihara T, Hasan MK, Taira K, Reddel RR, Kaul SC (2002b) A major functional difference between the mouse and human ARF tumor suppressor proteins. J Biol Chem 277:36665–36670

    Article  CAS  PubMed  Google Scholar 

  • Wadhwa R, Ando H, Kawasaki H, Taira K, Kaul SC (2003) Targeting mortalin using conventional and RNA-helicase-coupled hammerhead ribozymes. EMBO Rep 4:595–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wadhwa R, Takano S, Kaur K, Deocaris CC, Pereira-Smith OM, Reddel RR, Kaul SC (2006) Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis. Int J Cancer 118:2973–2980

    Article  CAS  PubMed  Google Scholar 

  • Wadhwa R, Ryu J, Ahn HM, Saxena N, Chaudhary A, Yun CO, Kaul SC (2015) Functional significance of point mutations in stress chaperone mortalin and their relevance to Parkinson disease. J Biol Chem 290:8447–8456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Blandino G, Givol D (1999) Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin. Oncogene 18:2643–2649

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Zhang X, Teng L, Legerski RJ (2015) DNA damage checkpoint recovery and cancer development. Exp Cell Res 334:350–358

    Article  CAS  PubMed  Google Scholar 

  • Wei S, Sedivy JM (1999) Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts. Cancer Res 59:1539–1543

    CAS  PubMed  Google Scholar 

  • Weyand CM, Fulbright JW, Goronzy JJ (2003) Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol 38:833–841

    Article  CAS  PubMed  Google Scholar 

  • Wlaschek M, Ma W, Jansen-Durr P, Scharffetter-Kochanek K (2003) Photoaging as a consequence of natural and therapeutic ultraviolet irradiation – studies on PUVA-induced senescence-like growth arrest of human dermal fibroblasts. Exp Gerontol 38:1265–1270

    Article  CAS  PubMed  Google Scholar 

  • Woods YL, Xirodimas DP, Prescott AR, Sparks A, Lane DP, Saville MK (2004) p14 Arf promotes small ubiquitin-like modifier conjugation of Werners helicase. J Biol Chem 279:50157–50166

    Article  CAS  PubMed  Google Scholar 

  • Wynford-Thomas D (1996) Telomeres, p53 and cellular senescence. Oncol Res 8:387–398

    CAS  PubMed  Google Scholar 

  • Xu HJ, Zhou Y, Ji W, Perng GS, Kruzelock R, Kong CT, Bast RC, Mills GB, Li J, Hu SX (1997) Reexpression of the retinoblastoma protein in tumor cells induces senescence and telomerase inhibition. Oncogene 15:2589–2596

    Article  CAS  PubMed  Google Scholar 

  • Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan S, Sorrell M, Berman Z (2014) Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress. Cell Mol Life Sci 71:3951–3967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo JY, Ryu J, Gao R, Yaguchi T, Kaul SC, Wadhwa R, Yun CO (2010) Tumor suppression by apoptotic and anti-angiogenic effects of mortalin-targeting adeno-oncolytic virus. J Gene Med 12:586–595

    Article  CAS  PubMed  Google Scholar 

  • Zannini L, Delia D, Buscemi G (2014) CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol 6:442–457

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Hunter T (2014) Roles of Chk1 in cell biology and cancer therapy. Int J Cancer 134:1013–1023

    Article  CAS  PubMed  Google Scholar 

  • Zhang DG, Zheng JN, Pei DS (2014) P53/microRNA-34-induced metabolic regulation: new opportunities in anticancer therapy. Mol Cancer 13:115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao L, Samuels T, Winckler S, Korgaonkar C, Tompkins V, Horne MC, Quelle DE (2003) Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways. Mol Cancer Res 1:195–206

    CAS  PubMed  Google Scholar 

  • Zhu J, Woods D, McMahon M, Bishop JM (1998) Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 12:2997–3007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zindy F, Williams RT, Baudino TA, Rehg JE, Skapek SX, Cleveland JL, Roussel MF, Sherr CJ (2003) Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc Natl Acad Sci U S A 100:15930–15935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Conflict of Interest

The authors declare that they have no competing interests to disclose.

Author information

Authors and Affiliations

  1. Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Biomedical Research Institute, National Institute of Advanced Industrial Science & Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki, 305 8565, Japan

    Renu Wadhwa

  2. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, 43210, USA

    Zeenia Kaul

  3. National Institute of Advanced Industrial Science & Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki, 305 8565, Japan

    Sunil C. Kaul

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  1. Renu Wadhwa
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  2. Zeenia Kaul
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Correspondence to Renu Wadhwa .

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Editors and Affiliations

  1. Dep of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

    Suresh I.S. Rattan

  2. Department of Anatomy,School of Medicine, University of California, San Francisco, USA

    Leonard Hayflick

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Wadhwa, R., Kaul, Z., Kaul, S.C. (2016). Cell Cycle Checkpoints and Senescence. In: Rattan, S., Hayflick, L. (eds) Cellular Ageing and Replicative Senescence. Healthy Ageing and Longevity. Springer, Cham. https://doi.org/10.1007/978-3-319-26239-0_9

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