Senescence and Cell Cycle Control

  • Hiroaki KiyokawaEmail author
Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 42)


In response to various stresses, such as telomere shortening during continuous proliferation, oxidative stress, DNA damage and aberrant oncogene activation, normal cells undergo cellular senescence, which is a stable postmitotic state with particular morphology and metabolism. Signaling that induces senescence involves two major tumor suppressor cascades, i.e., the INK4a-Rb pathway and the ARF-p53 pathway. Diverse stimuli upregulate these interacting pathways, which orchestrate exit from the cell cycle. Recent studies have provided insights into substantial differences in senescence-inducing signals in primary cells of human and rodent origins. This review is focused on recent advances in understanding the roles of the tumor-suppressive pathways in senescence.


Cellular Senescence Replicative Senescence Telomere Attrition Replicative Life Span Cell Cycle Reentry 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



I apologize to many colleagues for being unable to cite their papers critical for the field. I thank Nissim Hay, Rob Costa, Pradip Raychaudhuri, Oscar Colamonici, David Ucker and Xianghong Zou for helpful discussions, and the National Institutes of Health, the Department of Defense and the American Cancer Society for grant support for my research.


  1. 1.
    Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH (1998) p14ARF links the tumour suppressors RB and p53. Nature 395:124–125 PubMedCrossRefGoogle Scholar
  2. 2.
    Benanti JA, Galloway DA (2004) Normal human fibroblasts are resistant to RAS-induced senescence. Mol Cell Biol 24:2842–2852 PubMedCrossRefGoogle Scholar
  3. 3.
    Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P (2003) Cdk2 knockout mice are viable. Curr Biol 13:1775–1785 PubMedCrossRefGoogle Scholar
  4. 4.
    Boyle JM, Mitchell EL, Greaves MJ, Roberts SA, Tricker K, Burt E, Varley JM, Birch JM, Scott D (1998) Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families. Br J Cancer 77:2181–2192 PubMedCrossRefGoogle Scholar
  5. 5.
    Brookes S, Rowe J, Ruas M, Llanos S, Clark PA, Lomax M, James MC, Vatcheva R, Bates S, Vousden KH, Parry D, Gruis N, Smit N, Bergman W, Peters G (2002) INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J 21:2936–2945 PubMedCrossRefGoogle Scholar
  6. 6.
    Brookes S, Rowe J, Gutierrez DA, Bond J, Peters G (2004) Contribution of p16INK4a to replicative senescence of human fibroblasts. Exp Cell Res 298:549–559 PubMedCrossRefGoogle Scholar
  7. 7.
    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 PubMedCrossRefGoogle Scholar
  8. 8.
    Campisi J (2001) Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 11:S27–S31 PubMedGoogle Scholar
  9. 9.
    Carnero A, Hudson JD, Price CM, Beach DH (2000) p16INK4a and p19ARF act in overlapping pathways in cellular immortalization. Nat Cell Biol 2:148–155 PubMedCrossRefGoogle Scholar
  10. 10.
    Chang BD, Swift ME, Shen M, Fang J, Broude EV, Roninson IB (2002) Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc Natl Acad Sci USA 99:389–394 PubMedCrossRefGoogle Scholar
  11. 11.
    Chen Q, Ames BN (1994) Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci USA 91:4130–4134 PubMedCrossRefGoogle Scholar
  12. 12.
    Coats S, Whyte P, Fero ML, Lacy S, Chung G, Randel E, Firpo E, Roberts JM (1999) A new pathway for mitogen-dependent cdk2 regulation uncovered in p27Kip1-deficient cells. Curr Biol 9:163–173 PubMedCrossRefGoogle Scholar
  13. 13.
    d'Adda dF, 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 CrossRefGoogle Scholar
  14. 14.
    Dannenberg JH, van Rossum A, Schuijff L, te Riele H (2000) Ablation of the retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev 14:3051–3064 PubMedCrossRefGoogle Scholar
  15. 15.
    de Lange T (1998) Telomeres and senescence: ending the debate. Science 279:334–335 PubMedCrossRefGoogle Scholar
  16. 16.
    De Gregori J, Leone G, Miron A, Jakoi L, Nevins JR (1997) Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci USA 94:7245–7250 CrossRefGoogle Scholar
  17. 17.
    Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367 PubMedCrossRefGoogle Scholar
  18. 18.
    Dimri GP, Itahana K, Acosta M, Campisi J (2000) Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor. Mol Cell Biol 20:273–285 PubMedCrossRefGoogle Scholar
  19. 19.
    Dirac AM, Bernards R (2003) Reversal of senescence in mouse fibroblasts through lentiviral suppression of p53. J Biol Chem 278:11731–11734 PubMedCrossRefGoogle Scholar
  20. 20.
    Drayton S, Peters G (2002) Immortalisation and transformation revisited. Curr Opin Genet Dev 12:98–104 PubMedCrossRefGoogle Scholar
  21. 21.
    El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825 PubMedCrossRefGoogle Scholar
  22. 22.
    Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, Lowe SW (2000) PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14:2015–2027 PubMedGoogle Scholar
  23. 23.
    Gil J, Bernard D, Martinez D, Beach D (2004) Polycomb CBX7 has a unifying role in cellular lifespan. Nat Cell Biol 6:67–72 PubMedCrossRefGoogle Scholar
  24. 24.
    Gire V, Roux P, Wynford-Thomas D, Brondello JM, Dulic V (2004) DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J 23:2554–2563 PubMedCrossRefGoogle Scholar
  25. 25.
    Gonzalez-Suarez E, Flores JM, Blasco MA (2002) Cooperation between p53 mutation and high telomerase transgenic expression in spontaneous cancer development. Mol Cell Biol 22:7291–7301 PubMedCrossRefGoogle Scholar
  26. 26.
    Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, Beijersbergen RL, Knoll JH, Meyerson M, Weinberg RA (1999) Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5:1164–1170 PubMedCrossRefGoogle Scholar
  27. 27.
    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 PubMedCrossRefGoogle Scholar
  28. 28.
    Hatakeyama M, Weinberg RA (1995) The role of Rb in cell cycle control. Prog Cell Cycle Res 1:9–19 PubMedGoogle Scholar
  29. 29.
    Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621 CrossRefGoogle Scholar
  30. 30.
    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 p21CIP1, but not p16INK4a. Mol Cell 14:501–513 PubMedCrossRefGoogle Scholar
  31. 31.
    Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J, Dimri GP (2003) Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol 23:389–401 PubMedCrossRefGoogle Scholar
  32. 32.
    Itahana K, Campisi J, Dimri GP (2004) Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5:1–10 PubMedCrossRefGoogle Scholar
  33. 33.
    Iwasa H, Han J, Ishikawa F (2003) Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 8:131–144 PubMedCrossRefGoogle Scholar
  34. 34.
    Jacobs JJ, de Lange T (2004) Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol 14:2302–2308 PubMedCrossRefGoogle Scholar
  35. 35.
    Jacobs JJ, Kieboom K, Marino S, DePinho RA, Van Lohuizen M (1999) The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the INK4a locus. Nature 397:164–168 PubMedCrossRefGoogle Scholar
  36. 36.
    Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS III, Johnson BE, Skolnick MH (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440 PubMedCrossRefGoogle Scholar
  37. 37.
    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 PubMedCrossRefGoogle Scholar
  38. 38.
    Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ (1998) Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396:84–88 PubMedCrossRefGoogle Scholar
  39. 39.
    Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A (2001) Loss of p16INK4a confers susceptibility to metastatic melanoma in mice. Nature 413:83–86 PubMedCrossRefGoogle Scholar
  40. 40.
    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 PubMedCrossRefGoogle Scholar
  41. 41.
    Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty TD (1992) Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70:923–935 PubMedCrossRefGoogle Scholar
  42. 42.
    Lowe SW, Sherr CJ (2003) Tumor suppression by INK4a-ARF: progress and puzzles. Curr Opin Genet Dev 13:77–83 PubMedCrossRefGoogle Scholar
  43. 43.
    Lowe SW, Jacks T, Housman DE, Ruley HE (1994) Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. Proc Natl Acad Sci USA 91:2026–2030 PubMedCrossRefGoogle Scholar
  44. 44.
    Macip S, Igarashi M, Fang L, Chen A, Pan ZQ, Lee SW, Aaronson SA (2002) Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J 21:2180–2188 PubMedCrossRefGoogle Scholar
  45. 45.
    Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S, Dubus P, Barbacid M (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118:493–504 PubMedCrossRefGoogle Scholar
  46. 46.
    Martin-Caballero J, Flores JM, Garcia-Palencia P, Serrano M (2001) Tumor susceptibility of p21Waf1/Cip1-deficient mice. Cancer Res 61:6234–6238 PubMedGoogle Scholar
  47. 47.
    Miliani de Marval PL, Macias E, Rounbehler R, Sicinski P, Kiyokawa H, Johnson DG, Conti CJ, Rodriguez-Puebla ML (2004) Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues. Mol Cell Biol 24:7538–7547 CrossRefGoogle Scholar
  48. 48.
    Munger K, Howley PM (2002) Human papillomavirus immortalization and transformation functions. Virus Res 89:213–228 PubMedCrossRefGoogle Scholar
  49. 49.
    Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–716 PubMedCrossRefGoogle Scholar
  50. 50.
    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 PubMedCrossRefGoogle Scholar
  51. 51.
    Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E (2001) Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409:1067–1070 PubMedCrossRefGoogle Scholar
  52. 52.
    Ortega S, Malumbres M, Barbacid M (2002) Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 1602:73–87 PubMedGoogle Scholar
  53. 53.
    Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, Barbero JL, Malumbres M, Barbacid M (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35:25–31 PubMedCrossRefGoogle Scholar
  54. 54.
    Palmero I, Pantoja C, Serrano M (1998) p19ARF links the tumour suppressor p53 to Ras. Nature 395:125–126 PubMedCrossRefGoogle Scholar
  55. 55.
    Pantoja C, Serrano M (1999) Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras. Oncogene 18:4974–4982 PubMedCrossRefGoogle Scholar
  56. 56.
    Park IK, Morrison SJ, Clarke MF (2004) Bmi1, stem cells, and senescence regulation. J Clin Invest 113:175–179 PubMedCrossRefGoogle Scholar
  57. 57.
    Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5:741–747 PubMedCrossRefGoogle Scholar
  58. 58.
    Pelicci PG (2004) Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence? J Clin Invest 113:4–7 PubMedCrossRefGoogle Scholar
  59. 59.
    Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA (1998) The INK4a tumor suppressor gene product, p19ARF, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92:713–723 PubMedCrossRefGoogle Scholar
  60. 60.
    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 PubMedCrossRefGoogle Scholar
  61. 61.
    Rane SG, Cosenza SC, Mettus RV, Reddy EP (2002) Germ line transmission of the Cdk4R24C mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol 22:644–656 PubMedCrossRefGoogle Scholar
  62. 62.
    Rodriguez-Puebla ML, Miliani de Marval PL, LaCava M, Moons DS, Kiyokawa H, Conti JC (2002) CDK4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation. Am J Pathol 161:405–411 PubMedCrossRefGoogle Scholar
  63. 63.
    Roninson IB (2002) Oncogenic functions of tumour suppressor p21Waf1/Cip1/Sdi1: association with cell senescence and tumour-promoting activities of stromal fibroblasts. Cancer Lett 179:1–14 Google Scholar
  64. 64.
    Rowland BD, Denissov SG, Douma S, Stunnenberg HG, Bernards R, Peeper DS (2002) E2F transcriptional repressor complexes are critical downstream targets of p19ARF/p53-induced proliferative arrest. Cancer Cell 2:55–65 PubMedCrossRefGoogle Scholar
  65. 65.
    Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96:701–712 PubMedCrossRefGoogle Scholar
  66. 66.
    Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams B, Theodorou E, Jacks T (2000) Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalization. Genes Dev 14:3037–3050 PubMedCrossRefGoogle Scholar
  67. 67.
    Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T (2003) Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424:223–228 PubMedCrossRefGoogle Scholar
  68. 68.
    Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707 PubMedCrossRefGoogle Scholar
  69. 69.
    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 PubMedCrossRefGoogle Scholar
  70. 70.
    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 PubMedCrossRefGoogle Scholar
  71. 71.
    Sharpless NE, DePinho RA (2002) p53: Good cop/bad cop. Cell 110:9–12 PubMedCrossRefGoogle Scholar
  72. 72.
    Sharpless NE, DePinho RA (2004) Telomeres, stem cells, senescence, and cancer. J Clin Invest 113:160–168 PubMedCrossRefGoogle Scholar
  73. 73.
    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 PubMedCrossRefGoogle Scholar
  74. 74.
    Sherr CJ, DePinho RA (2000) Cellular senescence: mitotic clock or culture shock? Cell 102:407–410 PubMedCrossRefGoogle Scholar
  75. 75.
    Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512 PubMedCrossRefGoogle Scholar
  76. 76.
    Smogorzewska A, de Lange T (2004) Regulation of telomerase by telomeric proteins. Annu Rev Biochem 73:177–208 PubMedCrossRefGoogle Scholar
  77. 77.
    Sotillo R, Dubus P, Martin J, de La CE, Ortega S, Malumbres M, Barbacid M (2001) Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J 20:6637–6647 PubMedCrossRefGoogle Scholar
  78. 78.
    Stevaux O, Dyson NJ (2002) A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol 14:684–691 PubMedCrossRefGoogle Scholar
  79. 79.
    Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH, Peters G (1998) The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17:5001–5014 PubMedCrossRefGoogle Scholar
  80. 80.
    Vousden KH, Prives C (2005) p53 and prognosis: new insights and further complexity. Cell 120:7–10 PubMedGoogle Scholar
  81. 81.
    Wei W, Hemmer RM, Sedivy JM (2001) Role of p14ARF in replicative and induced senescence of human fibroblasts. Mol Cell Biol 21:6748–6757 PubMedCrossRefGoogle Scholar
  82. 82.
    Wu C, Miloslavskaya I, Demontis S, Maestro R, Galaktionov K (2004) Regulation of cellular response to oncogenic and oxidative stress by Seladin-1. Nature 432:640–645 PubMedCrossRefGoogle Scholar
  83. 83.
    Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704 PubMedCrossRefGoogle Scholar
  84. 84.
    Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:725–734 PubMedCrossRefGoogle Scholar
  85. 85.
    Zhu J, Woods D, McMahon M, Bishop JM (1998) Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 12:2997–3007 PubMedCrossRefGoogle Scholar
  86. 86.
    Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12:2424–2433 PubMedCrossRefGoogle Scholar
  87. 87.
    Zou X, Ray D, Aziyu A, Christov K, Boiko AD, Gudkov AV, Kiyokawa H (2002) Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to ARF/p53-independent senescence. Genes Dev 16:2923–2934 PubMedCrossRefGoogle Scholar

Authors and Affiliations

  1. 1.Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

Personalised recommendations