Biogerontology

, Volume 5, Issue 1, pp 1–10 | Cite as

Mechanisms of cellular senescence in human and mouse cells

  • Koji Itahana
  • Judith Campisi
  • Goberdhan P. Dimri
Article

Abstract

Telomere erosion is considered to be the main cause of the onset of replicative senescence. However, recent findings suggest that a senescent phenotype can be induced by a variety of other stimuli that act independently of telomeres. Moreover, telomere-dependent replicative senescence depends on the species of cell origin, in particular whether cells are of human or rodent origin. In addition, the tissue of origin may also dictate the pathway by which cells undergo replicative senescence. In this Review article, we categorize cellular senescence into two types, which for simplicity we term intrinsic or extrinsic senescence,focus on the differences between human and mouse cells, and discuss the roles of the p53 and pRb tumor suppressor pathways in cellular senescence.

p16 p53 pRb senescence telomere 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Afshari CA, Vojta PJ, Annab LA, Futreal PA, Willard TB and Barrett JC (1993) Investigation of the role of G1/S cell cycle mediators in cellular senescence. Exp Cell Res 209: 231- 237PubMedGoogle Scholar
  2. Atadja P, Wong H, Garkavstev I, Veillette C and Riabowol K (1995) Increased activity of p53 in senescing fibroblasts. Proc Natl Acad Sci USA 92: 8348-8352PubMedGoogle Scholar
  3. Bischof O, Kirsh O, Pearson M, Itahana K, Pelicci PG and Dejean A (2002) Deconstructing PML-induced premature senescence. EMBO J 21: 3358-3369PubMedGoogle Scholar
  4. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA and Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91: 25-34PubMedGoogle Scholar
  5. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S and Wright WE (1998) Extension of lifespan by introduction of telomerase into normal human cells. Science 279: 349-352PubMedGoogle Scholar
  6. Brenner AJ, Stampfer MR and Aldaz CM (1998) Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene 17: 199-205PubMedGoogle Scholar
  7. Brown JP, Wei W and Sedivy JM (1997) Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277: 831-834PubMedGoogle Scholar
  8. Campisi J (2000) Cancer, aging and cellular senescence. In vivo 14: 183-188PubMedGoogle Scholar
  9. Campisi J (2001) Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 11: 27-31Google Scholar
  10. Campisi J (2003) Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes. Exp Gerontol 38: 5-11PubMedGoogle Scholar
  11. Campisi J, Dimri GP and Hara E (1996) Control of replicative senescence. In: Schneider EL and Rowe JW (eds) Handbook of the Biology of Aging, 4th ed, pp 121-149. Academic Press, San Diego, CaliforniaGoogle Scholar
  12. Cao L, Li W, Kim S, Brodie SG and Deng CX (2003) Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform. Genes Dev 17: 201-213PubMedGoogle Scholar
  13. Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW and DePinho RA (1999) p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97: 527-538PubMedGoogle Scholar
  14. Choi J, Shendrik I, Peacocke M, Peehl D, Buttyan R, Ikeguchi EF, Katz AE and Benson MC (2000) Expression of senescenceassociated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia. Urology 56: 160-166PubMedGoogle Scholar
  15. Dannenberg JH, van Rossum A, Schuijff L and te Riele H (2000) Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions. Genes Dev 14: 3051-3064PubMedGoogle Scholar
  16. de Lange T (2002) Protection of mammalian telomeres. Oncogene 21: 532-540PubMedGoogle Scholar
  17. DiLeonardo A, Linke SP, Clarkin K and Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and longterm induction of Cip1 in normal human fibroblasts. Genes Dev 8: 2540-2551PubMedGoogle Scholar
  18. Dimri GP and Campisi J (1995) Molecular and cell biology of replicative senescence. Cold Spring Harbor Lab Symp Quant Biol Mol Genet Cancer 54: 67-73Google Scholar
  19. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith OM et al. (1995) A novel biomarker identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92: 9363-9367PubMedGoogle Scholar
  20. Dimri GP, Itahana K, Acosta M and Campisi J (2000) Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol Cell Biol 20: 273- 285PubMedGoogle Scholar
  21. Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM, Weill JC, Blasco MA and Serrano M (2002) “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 21: 6225-6235PubMedGoogle Scholar
  22. Gonzalez-Suarez E, Samper E, Flores JM and Blasco MA (2000) Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet 26: 114-117PubMedGoogle Scholar
  23. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H and de Lange T (1999) Mammalian telomeres end in a large duplex loop. Cell 97: 503-514PubMedGoogle Scholar
  24. Harley CB, Futcher AB and Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345: 458-460PubMedGoogle Scholar
  25. Harvey M, Sands AT, Weiss RS, Hegi ME, Wiseman RW, Pantazis P, Giovanella BC, Tainsky MA, Bradley A and Donehower LA (1993) In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8: 2457-2467PubMedGoogle Scholar
  26. Hayflick L and Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585-621.Google Scholar
  27. Itahana K, Dimri G and Campisi J (2001) Regulation of cellular senescence by p53. Eur J Biochem 268: 2784-2791PubMedGoogle Scholar
  28. Itahana K, Dimri GP, Hara E, Itahana Y, Zou Y, Desprez PY and Campisi J (2002) A role for p53 in maintaining and establishing the quiescence growth arrest in human cells. J Biol Chem 277: 18206-18214PubMedGoogle Scholar
  29. Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J and Dimri GP (2003) Control of the replicative lifespan of human fibroblasts by p16 and the polycomb protein bmi-1. Mol Cell Biol 23: 389-401PubMedGoogle Scholar
  30. Jacobs JJ, Kieboom K, Marino S, DePinho RA and van Lohuizen M (1999) The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397: 164-168PubMedGoogle Scholar
  31. Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing RA, Ashmun G, Grosveld G and Sherr CJ (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91: 649-659PubMedGoogle Scholar
  32. Karlseder J, Broccoli D, Dai Y, Hardy S and de Lange T (1999) p53-and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283: 1321-1325PubMedGoogle Scholar
  33. Kim SH, Kaminker P and Campisi J (2002) Telomeres, aging and cancer: in search of a happy ending. Oncogene 21: 503-511PubMedGoogle Scholar
  34. Korgaonkar C, Zhao L, Modestou M and Quelle DE (2002) ARF function does not require p53 stabilization or Mdm2 relocalization. Mol Cell Biol 22: 196-206PubMedGoogle Scholar
  35. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A and Berns A (2001) Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413: 83-86PubMedGoogle Scholar
  36. Krtolica A, Parrinello S, Lockett S, Desprez P Y and Campisi J (2001) Senescent fibroblats promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98: 12072-12077PubMedGoogle Scholar
  37. Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG and Kouzarides T (2002) Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21: 2383-2396PubMedGoogle Scholar
  38. Leri A, Franco S, Zacheo A, Barlucchi L, Chimenti S, Limana F, Nadal-Ginard B, Kajstura J, Anversa P and Blasco MA (2003) Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J 22: 131-139PubMedGoogle Scholar
  39. McClintock B (1941) The stability of broken ends of chromosomes in Zea mays. Genetics 26: 234-282Google Scholar
  40. Metcalfe JA, Parkhill J, Campbell L, Stacey M, Biggs P, Byrd PJ and Taylor AM (1996) Accelerated telomere shortening in ataxia telangiectasia. Nat Genet 13: 350-353PubMedGoogle Scholar
  41. Mishima K, Handa JT, Aotaki-Keen A, Lutty GA, Morse LS and Hjelmeland LM (1999). Senescence-associated beta-galactosidase histochemistry for the primate eye. Invest Ophthalmol Vis Sci 40: 1590-1593PubMedGoogle Scholar
  42. Morales CP, Holt SE, Ouellette M, Kaur KJ, Yan Y, Wilson KS, White MA, Wright WE and Shay JW (1999) Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat Genet 21: 115-118PubMedGoogle Scholar
  43. Niida H, Matsumoto T, Satoh H, Shiwa M, Tokutake Y, Furuichi Y and Shinkai Y (1998) Severe growth defect in mouse cells lacking the telomerase RNA component. Nat Genet 19: 203-206PubMedGoogle Scholar
  44. Noda A, Ning Y, Venable SF, Pereira-Smith OM and Smith JR (1994) Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 21: 90-98Google Scholar
  45. Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G and Hara E (2001) Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409: 1067-1070PubMedGoogle Scholar
  46. Packer L and Fuehr K (1977) Low oxygen concentration extends the lifespan of cultured human diploid cells. Nature 267: 423-425PubMedGoogle Scholar
  47. Pandita TK (2002) ATM function and telomere stability. Oncogene 21: 611-618PubMedGoogle Scholar
  48. Pantoja C and Serrano M (1999) Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras. Oncogene 18: 4974-4982PubMedGoogle Scholar
  49. Paradis V, Youssef N, Dargere D, Ba N, Bonvoust F and Bedossa P (2001) Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Hum Pathol 32: 327-332PubMedGoogle Scholar
  50. Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S and Campisi J (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nature Cell Biol 5: 741-747PubMedGoogle Scholar
  51. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP and Pelicci PG (2000) PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406: 207-210PubMedGoogle Scholar
  52. Pirrotta V (1998) Polycombing the genome: PcG, trxG, and chromatin silencing. Cell 93: 333-336PubMedGoogle Scholar
  53. Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW et al. (1998) The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92: 713-723PubMedGoogle Scholar
  54. Ramirez RD, Morales CP, Herbert BS, Rohde JM, Passons C, Shay JW and Wright WE (2001) Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev 15: 398-403PubMedGoogle Scholar
  55. Rane SG, Cosenza SC, Mettus RV and Reddy EP (2002) Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol 22: 644-656PubMedGoogle Scholar
  56. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C and DePinho RA (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96: 701-712PubMedGoogle Scholar
  57. Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM and Lowe SW (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109: 335-346PubMedGoogle Scholar
  58. Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams B, Theodorou E and Jacks T (2000) Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Genes Dev 14: 3037-3050PubMedGoogle Scholar
  59. Sage J, Miller AL, Pérez-Mancera PA, Wysocki JM and Jacks T (2003) Acute mutation of Rb is sufficient for cell cycle re-entry in quiescent and senescent cells. Nature 424: 223-228PubMedGoogle Scholar
  60. Saito H, Hammond AT and Moses RE (1995) The effect of low oxygen tension on the in vitro-replicative lifespan of human diploid fibroblast cells and their transformed derivatives. Exp Cell Res 217: 272-279PubMedGoogle Scholar
  61. Seger YR, Garcia-Cao M, Piccinin S, Cunsolo CL, Doglioni C, Blasco MA, Hannon GJ and Maestro R (2002) Transformation of normal human cells in the absence of telomerase activation. Cancer Cell 2: 401-413PubMedGoogle Scholar
  62. Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593-602PubMedGoogle Scholar
  63. Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW and DePinho RA (2001) Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413: 86-91PubMedGoogle Scholar
  64. Shelton DN, Chang E, Whittier PS, Choi D and Funk WD (1999) Microarray analysis of replicative senescence. Curr Biol 9: 939- 945PubMedGoogle Scholar
  65. Sherr CJ and DePinho RA (2000) Cellular senescence: Mitotic clock or culture shock? Cell 102: 407-410PubMedGoogle Scholar
  66. Stansel RM, Subramanian D and Griffith JD (2002) p53 binds telomeric single strand overhangs and t-loop junctions in vitro. JBiol Chem 277: 11625-11628Google Scholar
  67. Sugihara T, Kaul SC, Kato J, Reddel RR, Nomura H and Wadhwa R (2001) Pex19p dampens the p19ARF-p53-p21WAF1 tumor suppressor pathway. J Biol Chem 276: 18649-18652PubMedGoogle Scholar
  68. te Poele RH, Okorokov AL, Jardine L, Cummings J and Joel SP (2002) DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 62: 1876-1883PubMedGoogle Scholar
  69. 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: 45-53PubMedGoogle Scholar
  70. van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H, van der Valk M, Deschamps J, Sofroniew M, van Lohuizen M et al. (1994) Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 8: 757-769PubMedGoogle Scholar
  71. Vasile E, Tomita Y, Brown LF, Kocher O and Dvorak HF (2001) Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J 15: 458-466PubMedGoogle Scholar
  72. Vaupel P, Kallinowski F and Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49: 6449-6465PubMedGoogle Scholar
  73. Vaziri H, West MD, Allsopp RC, Davison TS, Wu YS, Arrowsmith CH, Poirier GG and Benchimol S (1997) ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. EMBO J 16: 6018- 6033PubMedGoogle Scholar
  74. Vaziri H, Squire JA, Pandita TK, Bradley G, Kuba RM, Zhang H, Gulyas S, Hill RP, Nolan GP and Benchimol S (1999) Analysis of genomic integrity and p53-dependent G1 checkpoint in telomerase-induced extended-lifespan human fibroblasts. Mol Cell Biol 19: 2373-2379PubMedGoogle Scholar
  75. Wadhwa R, Sugihara T, Hasan MK, Taira K, Reddel RR and Kaul SC (2002) A major functional difference between the mouse and human ARF tumor suppressor proteins. J Biol Chem 277: 36665-36670PubMedGoogle Scholar
  76. Webley K, Bond JA, Jones CJ, Blaydes JP, Craig A, Hupp T and Wynford-Thomas D (2000) Post-translational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol Cell Biol 20: 2803-2808PubMedGoogle Scholar
  77. Wei W, Hemmer RM and Sedivy JM (2001) Role of p14(ARF) in replicative and induced senescence of human fibroblasts. Mol Cell Biol 21: 6748-6757PubMedGoogle Scholar
  78. Williams G (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11: 398-411Google Scholar
  79. Wong DJ, Foster SA, Galloway DA and Reid BJ (1999) Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest. Mol Cell Biol 8: 5642-5651Google Scholar
  80. Wright WE and Shay JW (1996) Mechanism of escaping senescence in human diploid cells. In: Holbrook NJ, Martin GR and Lockshin R (eds) Modern Cell Biology Series - Cellular Aging and Cell Death, pp 153-167. Wiley & Sons, New YorkGoogle Scholar
  81. Wright WE and Shay JW (2000) Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nat Med 6: 849-851PubMedGoogle Scholar
  82. Yagita K, Tamanini F, van Der Horst GT and Okamura H (2001) Molecular mechanisms of the biological clock in cultured fibroblasts. Science 292: 278-281PubMedGoogle Scholar
  83. Zhang Y, Xiong Y and 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: 725-734PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Koji Itahana
    • 1
  • Judith Campisi
    • 2
  • Goberdhan P. Dimri
    • 3
  1. 1.Department of Molecular and Cellular OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Life Sciences Division, Lawrence Berkeley National LaboratoryBerkeleyUSA
  3. 3.Division of Cancer Biology, Department of MedicineEvanston Northwestern Healthcare Research InstituteEvanstonUSA

Personalised recommendations