Table of Contents Author Guidelines Submit a Manuscript
Journal of Aging Research
Volume 2011, Article ID 725365, 12 pages
http://dx.doi.org/10.4061/2011/725365
Review Article

Cellular Senescence as a Target in Cancer Control

1Instituto de Biomedicina de Sevilla, Hospital Universitario virgen del Rocio, 41013 Sevilla, Spain
2Department of Preventive Medicine and Public Heath, University of Seville, 41012 Seville, Spain
3Consejo Superior de Investigaciones Cientificas, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain

Received 27 September 2010; Accepted 3 November 2010

Academic Editor: Matilde E. LLeonart

Copyright © 2011 Mar Vergel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. L. Hayflick, “The limited in vitro lifetime of human diploid cell strains,” Experimental Cell Research, vol. 37, no. 3, pp. 614–636, 1965. View at Google Scholar · View at Scopus
  2. D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000. View at Google Scholar · View at Scopus
  3. G. Untergasser, H. B. Koch, A. Menssen, and H. Hermeking, “Characterization of epithelial senescence by serial analysis of gene expression: identification of genes potentially involved in prostate cancer,” Cancer Research, vol. 62, no. 21, pp. 6255–6262, 2002. View at Google Scholar · View at Scopus
  4. D. X. Mason, T. J. Jackson, and A. W. Lin, “Molecular signature of oncogenic ras-induced senescence,” Oncogene, vol. 23, no. 57, pp. 9238–9246, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. S. R. Schwarze, V. X. Fu, J. A. Desotelle, M. L. Kenowski, and D. F. Jarrard, “The identification of senescence-specific genes during the induction of senescence in prostate cancer cells,” Neoplasia, vol. 7, no. 9, pp. 816–823, 2005. View at Publisher · View at Google Scholar · View at Scopus
  6. J. W. Shay and I. B. Roninson, “Hallmarks of senescence in carcinogenesis and cancer therapy,” Oncogene, vol. 23, no. 16, pp. 2919–2933, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. E. Thomas, E. Al-Baker, S. Dropcova et al., “Different kinetics of senescence in human fibroblasts and peritoneal mesothelial cells,” Experimental Cell Research, vol. 236, no. 1, pp. 355–358, 1997. View at Publisher · View at Google Scholar · View at Scopus
  8. H. Rubin, “The disparity between human cell senescence in vitro and lifelong replication in vivo,” Nature Biotechnology, vol. 20, no. 7, pp. 675–681, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. W. F. Wright and J. W. Shay, “Time, telomeres and tumours: is cellular senescence more than an anticancer mechanism?” Trends in Cell Biology, vol. 5, no. 8, pp. 293–296, 1995. View at Publisher · View at Google Scholar · View at Scopus
  10. D. Kipling, D. Wynford-Thomas, C. J. Jones et al., “Telomere-dependent senescence,” Nature Biotechnology, vol. 17, no. 4, pp. 313–314, 1999. View at Google Scholar · View at Scopus
  11. A. M. Olovnikov, “A theory of marginotomy: the incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon,” Journal of Theoretical Biology, vol. 41, no. 1, pp. 181–190, 1973. View at Google Scholar · View at Scopus
  12. L. Ruiz, M. Traskine, I. Ferrer et al., “Characterization of the p53 response to oncogene-induced senescene,” PLoS One, vol. 3, no. 9, Article ID e3230, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. F. D'Adda Di Fagagna, “Living on a break: cellular senescence as a DNA-damage response,” Nature Reviews Cancer, vol. 8, no. 7, pp. 512–522, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Narita, S. Nũnez, E. Heard et al., “Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence,” Cell, vol. 113, no. 6, pp. 703–716, 2003. View at Publisher · View at Google Scholar · View at Scopus
  15. J. Campisi, “Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors,” Cell, vol. 120, no. 4, pp. 513–522, 2005. View at Publisher · View at Google Scholar · View at Scopus
  16. P. Castro, D. Giri, D. Lamb, and M. Ittmann, “Cellular senescence in the pathogenesis of benign prostatic hyperplasia,” Prostate, vol. 55, no. 1, pp. 30–38, 2003. View at Publisher · View at Google Scholar · View at Scopus
  17. C. Michaloglou, L. C. W. Vredeveld, W. J. Mooi, and D. S. Peeper, “BRAF in benign and malignant human tumours,” Oncogene, vol. 27, no. 7, pp. 877–895, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. A. Krtolica, S. Parrinello, S. Lockett, P. Y. Desprez, and J. Campisi, “Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 21, pp. 12072–12077, 2001. View at Publisher · View at Google Scholar · View at Scopus
  19. C. Bavik, I. Coleman, J. P. Dean, B. Knudsen, S. Plymate, and P. S. Nelson, “The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms,” Cancer Research, vol. 66, no. 2, pp. 794–802, 2006. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Parrinello, J. P. Coppe, A. Krtolica, and J. Campisi, “Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation,” Journal of Cell Science, vol. 118, no. 3, pp. 485–496, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. J. P. Coppé, C. K. Patil, F. Rodier et al., “A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen,” PLoS One, vol. 5, no. 2, Article ID e9188, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. J. P. Coppé, C. K. Patil, F. Rodier et al., “Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor,” PLoS Biology, vol. 6, no. 12, pp. 2853–2868, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. J. P. Coppé, P. Y. Desprez, A. Krtolica, and J. Campisi, “The senescence-associated secretory phenotype: the dark side of tumor suppression,” Annual Review of Pathology, vol. 5, pp. 99–118, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. A. R. Davalos, J. P. Coppe, J. Campisi, and P. Y. Desprez, “Senescent cells as a source of inflammatory factors for tumor progression,” Cancer and Metastasis Reviews, vol. 29, pp. 273–283, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Collado and M. Serrano, “The power and the promise of oncogene-induced senescence markers,” Nature Reviews Cancer, vol. 6, no. 6, pp. 472–476, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. A. Carnero, W. Link, J. F. Martinez et al., “Cellular senescence and cancer,” Advances in Cancer Research, vol. 3, pp. 183–198, 2003. View at Google Scholar
  27. C. Chandeck and W. J. Mooi, “Oncogene-induced cellular senescence,” Advances in Anatomic Pathology, vol. 17, no. 1, pp. 42–48, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. M. Braig and C. A. Schmitt, “Oncogene-induced senescence: putting the brakes on tumor development,” Cancer Research, vol. 66, no. 6, pp. 2881–2884, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Courtois-Cox, S. L. Jones, and K. Cichowski, “Many roads lead to oncogene-induced senescence,” Oncogene, vol. 27, no. 20, pp. 2801–2809, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. J. Bartek, J. Bartkova, and J. Lukas, “DNA damage signalling guards against activated oncogenes and tumour progression,” Oncogene, vol. 26, no. 56, pp. 7773–7779, 2007. View at Publisher · View at Google Scholar · View at Scopus
  31. Y. Ruzankina, A. Asare, and E. J. Brown, “Replicative stress, stem cells and aging,” Mechanisms of Ageing and Development, vol. 129, no. 7-8, pp. 460–466, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. J. Kenyon and S. L. Gerson, “The role of DNA damage repair in aging of adult stem cells,” Nucleic Acids Research, vol. 35, no. 22, pp. 7557–7565, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. R. Di Micco, M. Fumagalli, A. Cicalese et al., “Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication,” Nature, vol. 444, no. 7119, pp. 638–642, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. J. F. Passos and T. Von Zglinicki, “Oxygen free radicals in cell senescence: are they signal transducers?” Free Radical Research, vol. 40, no. 12, pp. 1277–1283, 2006. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Parrinello, E. Samper, A. Krtolica, J. Goldstein, S. Melov, and J. Campisi, “Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts,” Nature Cell Biology, vol. 5, no. 8, pp. 741–747, 2003. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Vergel and A. Carnero, “Bypassing cellular senescence by genetic screening tools,” Clinical and Translational Oncology, vol. 12, no. 6, pp. 410–417, 2010. View at Publisher · View at Google Scholar
  37. M. Malumbres and A. Carnero, “Cell cycle deregulation: a common motif in cancer,” Progress in Cell Cycle Research, vol. 5, pp. 5–18, 2003. View at Google Scholar · View at Scopus
  38. J. R. Smith and O. M. Pereira-Smith, “Replicative senescence: implications for in vivo aging and tumor suppression,” Science, vol. 273, no. 5271, pp. 63–67, 1996. View at Google Scholar · View at Scopus
  39. E. L. Duncan, N. J. Whitaker, E. L. Moy, and R. R. Reddel, “Assignment of SV40-immortalized cells to more than one complementation group for immortalization,” Experimental Cell Research, vol. 205, no. 2, pp. 337–344, 1993. View at Publisher · View at Google Scholar · View at Scopus
  40. J. C. Barrett, L. A. Annab, D. Alcorta, G. Preston, P. Vojta, and Y. Yin, “Cellular senescence and cancer,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 59, pp. 411–418, 1994. View at Google Scholar · View at Scopus
  41. M. Serrano and M. A. Blasco, “Putting the stress on senescence,” Current Opinion in Cell Biology, vol. 13, no. 6, pp. 748–753, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. C. A. Schmitt, “Cellular senescence and cancer treatment,” Biochimica et Biophysica Acta, vol. 1775, no. 1, pp. 5–20, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. W. J. Mooi and D. S. Peeper, “Oncogene-induced cell senescence—halting on the road to cancer,” New England Journal of Medicine, vol. 355, no. 10, pp. 1037–1046, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Carnero and M. E. Lleonart, “Epigenetic mechanisms in senescence, immortalisation and cancer,” Biological Reviews of the Cambridge Philosophical Society. In press.
  45. M. E. Castro, I. Ferrer, A. Cascón et al., “PPP1CA contributes to the senescence program induced by oncogenic Ras,” Carcinogenesis, vol. 29, no. 3, pp. 491–499, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. J. F. Leal, I. Ferrer, C. Blanco-Aparicio et al., “S-adenosylhomocysteine hydrolase downregulation contributes to tumorigenesis,” Carcinogenesis, vol. 29, no. 11, pp. 2089–2095, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. M. E. LLeonart, F. Vidal, D. Gallardo et al., “New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas,” Oncology Reports, vol. 16, no. 3, pp. 603–608, 2006. View at Google Scholar · View at Scopus
  48. J. F. M. Leal, J. Fominaya, A. Cascón et al., “Cellular senescence bypass screen identifies new putative tumor suppressor genes,” Oncogene, vol. 27, no. 14, pp. 1961–1970, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. H. Kondoh, M. E. Lleonart, J. Gil et al., “Glycolytic enzymes can modulate cellular life span,” Cancer Research, vol. 65, no. 1, pp. 177–185, 2005. View at Google Scholar · View at Scopus
  50. A. L. Fridman, R. Rosati, Q. Li, and M. A. Tainsky, “Epigenetic and functional analysis of IGFBP3 and IGFBPrP1 in cellular immortalization,” Biochemical and Biophysical Research Communications, vol. 357, no. 3, pp. 785–791, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. R. M. Kortlever and R. Bernards, “Senescence, wound healing and cancer: the PAI-1 connection,” Cell Cycle, vol. 5, no. 23, pp. 2697–2703, 2006. View at Google Scholar · View at Scopus
  52. R. M. Kortlever, P. J. Higgins, and R. Bernards, “Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence,” Nature Cell Biology, vol. 8, no. 8, pp. 877–884, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. W. Wang, J. X. Chen, R. Liao et al., “Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence,” Molecular and Cellular Biology, vol. 22, no. 10, pp. 3389–3403, 2002. View at Publisher · View at Google Scholar · View at Scopus
  54. R. Haq, J. D. Brenton, M. Takahashi, D. Finan, R. Rottapel, and B. Zanke, “Constitutive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence,” Cancer Research, vol. 62, no. 17, pp. 5076–5082, 2002. View at Google Scholar
  55. H. Zhang and S. N. Cohen, “Smurf2 up-regulation activates telomere-dependent senescence,” Genes and Development, vol. 18, no. 24, pp. 3028–3040, 2004. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Shibanuma, E. Mochizuki, R. Maniwa et al., “Induction of senescence-like phenotypes by forced expression of hic-5, which encodes a novel LIM motif protein, in immortalized human fibroblasts,” Molecular and Cellular Biology, vol. 17, no. 3, pp. 1224–1235, 1997. View at Google Scholar · View at Scopus
  57. J. Campisi and F. D'Adda Di Fagagna, “Cellular senescence: when bad things happen to good cells,” Nature Reviews Molecular Cell Biology, vol. 8, no. 9, pp. 729–740, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. D. Wynford-Thomas, “p53: guardian of cellular senescence,” Journal of Pathology, vol. 180, no. 2, pp. 118–121, 1996. View at Publisher · View at Google Scholar · View at Scopus
  59. J. Bond, M. Haughton, J. Blaydes, V. Gire, D. Wynford-Thomas, and F. Wyllie, “Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence,” Oncogene, vol. 13, no. 10, pp. 2097–2104, 1996. View at Google Scholar · View at Scopus
  60. L. Chin, S. E. Artandi, Q. Shen et al., “p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis,” Cell, vol. 97, no. 4, pp. 527–538, 1999. View at Publisher · View at Google Scholar · View at Scopus
  61. M. Ashcroft, Y. Taya, and K. H. Vousden, “Stress signals utilize multiple pathways to stabilize p53,” Molecular and Cellular Biology, vol. 20, no. 9, pp. 3224–3233, 2000. View at Publisher · View at Google Scholar · View at Scopus
  62. J. P. Blaydes and D. Wynford-Thomas, “The proliferation of normal human fibroblasts is dependent upon negative regulation of p53 function by mdm2,” Oncogene, vol. 16, no. 25, pp. 3317–3322, 1998. View at Google Scholar · View at Scopus
  63. T. Kamijo, F. Zindy, M. F. Roussel et al., “Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19(ARF),” Cell, vol. 91, no. 5, pp. 649–659, 1997. View at Google Scholar · View at Scopus
  64. A. Carnero, J. D. Hudson, C. M. Price, and D. H. Beach, “p16(INK4A) and p19(ARF) act in overlapping pathways in cellular immortalization,” Nature Cell Biology, vol. 2, no. 3, pp. 148–155, 2000. View at Publisher · View at Google Scholar · View at Scopus
  65. A. Carnero and D. H. Beach, “Absence of p21 cooperates with c-myc in bypassing Ras-induced senescence and enhances oncogenic cooperation,” Oncogene, vol. 23, no. 35, pp. 6006–6011, 2004. View at Publisher · View at Google Scholar · View at Scopus
  66. C. Pantoja and M. Serrano, “Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras,” Oncogene, vol. 18, no. 35, pp. 4974–4982, 1999. View at Publisher · View at Google Scholar · View at Scopus
  67. J. P. Brown, W. Wei, and J. M. Sedivy, “Bypass of senescenoe after disruption of p21(CIP1)/(WAF1) gene in normal diploid human fibroblasts,” Science, vol. 277, no. 5327, pp. 831–834, 1997. View at Publisher · View at Google Scholar · View at Scopus
  68. J. S. L. Ho, W. Ma, D. Y. L. Mao, and S. Benchimol, “p53-dependent transcriptional repression of c-myc is required for G cell cycle arrest,” Molecular and Cellular Biology, vol. 25, no. 17, pp. 7423–7431, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. D. F. Jarrard, S. Sarkar, Y. Shi et al., “p16/pRb pathway alterations are required for bypassing senescence in human prostate epithelial cells,” Cancer Research, vol. 59, no. 12, pp. 2957–2964, 1999. View at Google Scholar · View at Scopus
  70. S. Haferkamp, S. L. Tran, T. M. Becker, L. L. Scurr, R. F. Kefford, and H. Rizos, “The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence,” Aging, vol. 1, no. 6, pp. 542–556, 2009. View at Google Scholar · View at Scopus
  71. X. Ye, B. Zerlanko, R. Zhang et al., “Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci,” Molecular and Cellular Biology, vol. 27, no. 7, pp. 2452–2465, 2007. View at Publisher · View at Google Scholar · View at Scopus
  72. G. Mulligan and T. Jacks, “The retinoblastoma gene family: cousins with overlapping interests,” Trends in Genetics, vol. 14, no. 6, pp. 223–229, 1998. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Carnero and G. J. Hannon, “The INK4 family of CDK inhibitors,” Current Topics in Microbiology and Immunology, vol. 227, pp. 43–56, 1997. View at Google Scholar · View at Scopus
  74. I. Palmero, B. McConnell, D. Parry et al., “Accumulation of p16(INK4a) in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status,” Oncogene, vol. 15, no. 5, pp. 495–503, 1997. View at Google Scholar · View at Scopus
  75. A. Okamoto, D. J. Demetrick, E. A. Spillare et al., “p16(INK4)mutations and altered expression in human tumors and cell lines,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 59, pp. 49–57, 1994. View at Google Scholar · View at Scopus
  76. P. Krimpenfort, K. C. Quon, W. J. Mooi, A. Loonstra, and A. Berns, “Loss of p16 confers susceptibility to metastatic melanoma in mice,” Nature, vol. 413, no. 6851, pp. 83–86, 2001. View at Publisher · View at Google Scholar · View at Scopus
  77. N. E. Sharpless, N. Bardeesy, K. H. Lee et al., “Loss of p16 with retention of p19 predisposes mice to tumorigenesis,” Nature, vol. 413, no. 6851, pp. 86–91, 2001. View at Publisher · View at Google Scholar · View at Scopus
  78. B. Amati, K. Alevizopoulos, and J. Vlach, “Myc and the cell cycle,” Frontiers in Bioscience, vol. 3, pp. d250–d268, 1998. View at Google Scholar · View at Scopus
  79. J. Wang, L. Y. Xie, S. Allan, D. Beach, and G. J. Hannon, “Myc activates telomerase,” Genes and Development, vol. 12, no. 12, pp. 1769–1774, 1998. View at Google Scholar · View at Scopus
  80. J. Gil, P. Kerai, M. Lleonart et al., “Immortalization of primary human prostate epithelial cells by c-Myc,” Cancer Research, vol. 65, no. 6, pp. 2179–2185, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. S. B. Baylin, S. A. Belinsky, and J. G. Herman, “Aberrant methylation of gene promoters in cancer—concepts, misconcepts, and promise,” Journal of the National Cancer Institute, vol. 92, no. 18, pp. 1460–1461, 2000. View at Google Scholar · View at Scopus
  82. T. R. Brummelkamp, K. Berns, E. M. Hijmans et al., “Functional identification of cancer-relevant genes through large-scale RNA interference screens in mammalian cells,” Cold Spring Harbor Symposia on Quantitative Biology, vol. 69, pp. 439–445, 2004. View at Publisher · View at Google Scholar · View at Scopus
  83. C. Michaloglou, L. C. W. Vredeveld, M. S. Soengas et al., “BRAF-associated senescence-like cell cycle arrest of human naevi,” Nature, vol. 436, no. 7051, pp. 720–724, 2005. View at Publisher · View at Google Scholar · View at Scopus
  84. M. Collado, J. Gil, A. Efeyan et al., “Tumour biology: senescence in premalignant tumours,” Nature, vol. 436, no. 7051, p. 642, 2005. View at Publisher · View at Google Scholar · View at Scopus
  85. E. L. Denchi, C. Attwooll, D. Pasini, and K. Helin, “Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland,” Molecular and Cellular Biology, vol. 25, no. 7, pp. 2660–2672, 2005. View at Publisher · View at Google Scholar · View at Scopus
  86. Z. Chen, L. C. Trotman, D. Shaffer et al., “Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis,” Nature, vol. 436, no. 7051, pp. 725–730, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. M. Braig, S. Lee, C. Loddenkemper et al., “Oncogene-induced senescence as an initial barrier in lymphoma development,” Nature, vol. 436, no. 7051, pp. 660–665, 2005. View at Publisher · View at Google Scholar · View at Scopus
  88. I. B. Roninson, “Tumor cell senescence in cancer treatment,” Cancer Research, vol. 63, no. 11, pp. 2705–2715, 2003. View at Google Scholar · View at Scopus
  89. O. M. Pereira-Smith and J. R. Smith, “Genetic analysis of indefinite division in human cells: identification of four complementation groups,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 16, pp. 6042–6046, 1988. View at Google Scholar · View at Scopus
  90. B. B. McConnell, M. Starborg, S. Brookes, and G. Peters, “Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts,” Current Biology, vol. 8, no. 6, pp. 351–354, 1998. View at Google Scholar · View at Scopus
  91. A. Carnero, J. D. Hudson, G. J. Hannon, and D. H. Beach, “Loss-of-function genetics in mammalian cells: the p53 tumor suppressor model,” Nucleic Acids Research, vol. 28, no. 11, pp. 2234–2241, 2000. View at Google Scholar · View at Scopus
  92. A. Carnero, “Targeting the cell cycle for cancer therapy,” British Journal of Cancer, vol. 87, no. 2, pp. 129–133, 2002. View at Publisher · View at Google Scholar · View at Scopus
  93. K. L. Ball, S. Lain, R. Fåhraeus, C. Smythe, and D. P. Lane, “Cell-cycle arrest and inhibition of Cdk4 activity by small peptides based on the carboxy-terminal domain of p21(WAF1),” Current Biology, vol. 7, no. 1, pp. 71–80, 1997. View at Google Scholar · View at Scopus
  94. C. A. Schmitt, J. S. Fridman, M. Yang et al., “A senescence program controlled by p53 and p16 contributes to the outcome of cancer therapy,” Cell, vol. 109, no. 3, pp. 335–346, 2002. View at Publisher · View at Google Scholar · View at Scopus
  95. S. W. Lowe, H. E. Ruley, T. Jacks, and D. E. Housman, “p53-Dependent apoptosis modulates the cytotoxicity of anticancer agents,” Cell, vol. 74, no. 6, pp. 957–967, 1993. View at Publisher · View at Google Scholar · View at Scopus
  96. S. W. Lowe, E. Cepero, and G. Evan, “Intrinsic tumour suppression,” Nature, vol. 432, no. 7015, pp. 307–315, 2004. View at Publisher · View at Google Scholar · View at Scopus
  97. I. B. Roninson, “Tumor senescence as a determinant of drug response in vivo,” Drug Resistance Updates, vol. 5, no. 5, pp. 204–208, 2002. View at Publisher · View at Google Scholar · View at Scopus
  98. R. H. te Poele, A. L. Okorokov, L. Jardine, J. Cummings, and S. P. Joel, “DNA damage is able to induce senescence in tumor cells in vitro and in vivo,” Cancer Research, vol. 62, no. 6, pp. 1876–1883, 2002. View at Google Scholar · View at Scopus
  99. K. W. Maloney, L. McGavran, L. F. Odom, and S. P. Hunger, “Acquisition of p16(INK4A) and p15(INK4B) gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia,” Blood, vol. 93, no. 7, pp. 2380–2385, 1999. View at Google Scholar · View at Scopus
  100. T. L. Carter, P. M. Watt, R. Kumar et al., “Hemizygous p16 deletion in pediatric acute lymphoblastic leukemia predicts independent risk of relapse,” Blood, vol. 97, no. 2, pp. 572–574, 2001. View at Publisher · View at Google Scholar · View at Scopus
  101. K. S. J. Elenitoba-Johnson, R. D. Gascoyne, M. S. Lim, M. Chhanabai, E. S. Jaffe, and M. Raffeld, “Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma,” Blood, vol. 91, no. 12, pp. 4677–4685, 1998. View at Google Scholar · View at Scopus
  102. Q. M. Chen, “Replicative senescence and oxidant-induced premature senescence. Beyond the control of cell cycle checkpoints,” Annals of the New York Academy of Sciences, vol. 908, pp. 111–125, 2000. View at Google Scholar · View at Scopus
  103. B.-D. Chang, E. V. Broude, M. Dokmanovic et al., “A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents,” Cancer Research, vol. 59, no. 15, pp. 3761–3767, 1999. View at Google Scholar
  104. X. Wang, S. C. H. Wong, J. Pan et al., “Evidence of cisplatin-induced senescent-like growth arrest in nasopharyngeal carcinoma cells,” Cancer Research, vol. 58, no. 22, pp. 5019–5022, 1998. View at Google Scholar · View at Scopus
  105. E. J. Yeo, Y. C. Hwang, C. M. Kang et al., “Senescence-like changes induced by hydroxyurea in human diploid fibroblasts,” Experimental Gerontology, vol. 35, no. 5, pp. 553–571, 2000. View at Publisher · View at Google Scholar · View at Scopus
  106. E. Michishita, K. Nakabayashi, T. Suzuki et al., “5-Bromodeoxyuridine induces senescence-like phenomena in mammalian cells regardless of cell type or species,” Journal of Biochemistry, vol. 126, no. 6, pp. 1052–1059, 1999. View at Google Scholar · View at Scopus
  107. B. D. Chang, Y. Xuan, E. V. Broude et al., “Role of p53 and p21(waf1/cip1) in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs,” Oncogene, vol. 18, no. 34, pp. 4808–4818, 1999. View at Publisher · View at Google Scholar · View at Scopus
  108. L. W. Elmore, C. W. Rehder, X. Di et al., “Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction,” Journal of Biological Chemistry, vol. 277, no. 38, pp. 35509–35515, 2002. View at Publisher · View at Google Scholar · View at Scopus
  109. V. Gire, P. Roux, D. Wynford-Thomas, J. M. Brondello, and V. Dulic, “DNA damage checkpoint kinase Chk2 triggers replicative senescence,” EMBO Journal, vol. 23, no. 13, pp. 2554–2563, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. O. Moiseeva, F. A. Mallette, U. K. Mukhopadhyay, A. Moores, and G. Ferbeyre, “DNA damage signaling and p53-dependent senescence after prolonged β-interferon stimulation,” Molecular Biology of the Cell, vol. 17, no. 4, pp. 1583–1592, 2006. View at Publisher · View at Google Scholar
  111. S. I. Wells, D. A. Francis, A. Y. Karpova, J. J. Dowhanick, J. D. Benson, and P. M. Howley, “Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways,” EMBO Journal, vol. 19, no. 21, pp. 5762–5771, 2000. View at Google Scholar · View at Scopus
  112. D. Lodygin, A. Menssen, and H. Hermeking, “Induction of the Cdk inhibitor p21 by LY83583 inhibits tumor cell proliferation in a p53-independent manner,” Journal of Clinical Investigation, vol. 110, no. 11, pp. 1717–1727, 2002. View at Publisher · View at Google Scholar · View at Scopus
  113. I. B. Roninson and M. Dokmanovic, “Induction of senescence-associated growth inhibitors in the tumor-suppressive function of retinoids,” Journal of Cellular Biochemistry, vol. 88, no. 1, pp. 83–94, 2003. View at Publisher · View at Google Scholar · View at Scopus
  114. N. W. Kim, M. A. Piatyszek, K. R. Prowse et al., “Specific association of human telomerase activity with immortal cells and cancer,” Science, vol. 266, no. 5193, pp. 2011–2015, 1994. View at Google Scholar · View at Scopus
  115. W. C. Hahn, S. A. Stewart, M. W. Brooks et al., “Inhibition of telomerase limits the growth of human cancer cells,” Nature Medicine, vol. 5, no. 10, pp. 1164–1170, 1999. View at Publisher · View at Google Scholar · View at Scopus
  116. M. A. Blasco, H. W. Lee, M. P. Hande et al., “Telomere shortening and tumor formation by mouse cells lacking telomerase RNA,” Cell, vol. 91, no. 1, pp. 25–34, 1997. View at Publisher · View at Google Scholar · View at Scopus
  117. K. L. Rudolph, S. Chang, H. W. Lee et al., “Longevity, stress response, and cancer in aging telomerase-deficient mice,” Cell, vol. 96, no. 5, pp. 701–712, 1999. View at Google Scholar · View at Scopus
  118. T. J. Vulliamy, A. Marrone, S. W. Knight, A. Walne, P. J. Mason, and I. Dokal, “Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation,” Blood, vol. 107, no. 7, pp. 2680–2685, 2006. View at Publisher · View at Google Scholar
  119. R. Marciniak and L. Guarente, “Human genetics: testing telomerase,” Nature, vol. 413, no. 6854, pp. 370–373, 2001. View at Publisher · View at Google Scholar · View at Scopus
  120. S. E. Artandi and R. A. DePinho, “Mice without telomerase: what can they teach us about human cancer?” Nature Medicine, vol. 6, no. 8, pp. 852–855, 2000. View at Publisher · View at Google Scholar · View at Scopus
  121. S. E. Holt, W. E. Wright, and J. W. Shay, “Multiple pathways for the regulation of telomerase activity,” European Journal of Cancer A, vol. 33, no. 5, pp. 761–766, 1997. View at Publisher · View at Google Scholar · View at Scopus
  122. X. Zhang, V. Mar, W. Zhou, L. Harrington, and M. O. Robinson, “Telomere shortening and apoptosis in telomerase-inhibited human tumor cells,” Genes and Development, vol. 13, no. 18, pp. 2388–2399, 1999. View at Publisher · View at Google Scholar · View at Scopus