, 36:9637 | Cite as

A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging

  • David M. Nelson
  • Tony McBryan
  • Jessie C. Jeyapalan
  • John M. Sedivy
  • Peter D. AdamsEmail author


Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging.


Replicative senescence Oncogene-induced senescence Gene expression Cancer Aging 



Microarray sample preparation and Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray hybridization and scanning were conducted by the Paterson Institute for Cancer Research Microarray Service (Manchester, UK). Work in the lab of PDA was funded by BBSRC, and work in the lab of JMS was funded by NIA, as part of a joint-funding NIA/BBSRC partnership.

Data files

Accession number for RS array GSE36640 (

Accession number for OIS array GSE54402 (

Supplementary material

11357_2014_9637_MOESM1_ESM.pdf (757 kb)
Supplementary Figure 1 Confirmation of RS and OIS. (A) Proliferation curve for IMR90 cells cultured to RS. (B) SA β-gal staining of proliferating and RS IMR90 cells. (C) Whole cell lysates from proliferating and RS IMR90 cells were fractionated by SDS-PAGE and Western blotted for markers of proliferation and senescence. GAPDH serves as a loading control. (D) SA β-gal staining of control and H-RASG12V-infected IMR90 cells. (E) Whole cell lysates from control and H-RASG12V-infected IMR90 cells were fractionated by SDS-PAGE and Western blotted for markers of proliferation and senescence. GAPDH serves as a loading control. (PDF 757 kb)
11357_2014_9637_MOESM2_ESM.pdf (50 kb)
Supplementary Figure 2 Principal component analysis (PCA) of microarray expression datasets. (A) PCA shows that major separation of array datasets is according to proliferating (PD28) versus RS (PD90). (B) PCA shows that major separation of array datasets is according to control infection versus H-RAS infection (OIS). (PDF 49 kb)
11357_2014_9637_MOESM3_ESM.pdf (1.7 mb)
Supplementary Figure 3 Unsupervised clustering of microarray expression datasets. (A) Unsupervised clustering shows that major separation of array datasets is according to control infection versus H-RAS infection (OIS). (B) Unsupervised clustering shows that major separation of array datasets is according to proliferating (PD28) versus RS (PD90). (PDF 1784 kb)
11357_2014_9637_MOESM4_ESM.xls (4.9 mb)
ESM 4 (XLS 5004 kb)


  1. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, AddadiFagagna F, Bernard D, Hernando E, Gil J (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133(6):1006–1018. doi: 10.1016/j.cell.2008.03.038 PubMedCrossRefGoogle Scholar
  2. Adams PD (2009) Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol Cell 36(1):2–14. doi: 10.1016/j.molcel.2009.09.021 PubMedCrossRefGoogle Scholar
  3. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479 (7372):232–236. doi: 10.1038/nature10600 Google Scholar
  4. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Orntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444(7119):633–637PubMedCrossRefGoogle Scholar
  5. Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6(8):611–622. doi: 10.1038/nrg1656 PubMedCrossRefGoogle Scholar
  6. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279(5349):349–352PubMedCrossRefGoogle Scholar
  7. 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(7051):660–665PubMedCrossRefGoogle Scholar
  8. Burton DG, Giles PJ, Sheerin AN, Smith SK, Lawton JJ, Ostler EL, Rhys-Williams W, Kipling D, Faragher RG (2009) Microarray analysis of senescent vascular smooth muscle cells: A link to atherosclerosis and vascular calcification. Exp Gerontol 44(10):659–665. doi: 10.1016/j.exger.2009.07.004 PubMedCrossRefGoogle Scholar
  9. Chen WV, Maniatis T (2013) Clustered protocadherins. Development 140(16):3297–3302. doi: 10.1242/dev.090621 PubMedCrossRefGoogle Scholar
  10. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436(7051):725–730PubMedCentralPubMedCrossRefGoogle Scholar
  11. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M (2005) Tumour biology: senescence in premalignant tumours. Nature 436(7051):642PubMedCrossRefGoogle Scholar
  12. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6 (12):2853–2868. doi: 10.1371/journal.pbio.0060301 Google Scholar
  13. Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118. doi: 10.1146/annurev-pathol-121808-102144 PubMedCrossRefGoogle Scholar
  14. Cosme-Blanco W, Shen MF, Lazar AJ, Pathak S, Lozano G, Multani AS, Chang S (2007) Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep 8(5):497–503PubMedCentralPubMedCrossRefGoogle Scholar
  15. 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(6):459–472PubMedCentralPubMedCrossRefGoogle Scholar
  16. d'Adda di Fagagna F (2008) Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8 (7):512–522Google Scholar
  17. 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(20):9363–9367PubMedCentralPubMedCrossRefGoogle Scholar
  18. Feldser DM, Greider CW (2007) Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11(5):461–469PubMedCentralPubMedCrossRefGoogle Scholar
  19. Freund A, Laberge RM, Demaria M, Campisi J (2012) Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell. doi: 10.1091/mbc.E11-10-0884
  20. Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G (1996) Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol Cell Biol 16(3):859–867PubMedCentralPubMedGoogle Scholar
  21. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621PubMedCrossRefGoogle Scholar
  22. Jeyapalan JC, Sedivy JM (2013) How to measure RNA expression in rare senescent cells expressing any specific protein such as p16Ink4a. Aging (Albany NY) 5(2):120–129Google Scholar
  23. Jun JI, Lau LF (2010) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 12(7):676–685. doi: 10.1038/ncb2070 PubMedCentralPubMedCrossRefGoogle Scholar
  24. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwalder M, Khan S, Gil J, Bruder D, Manns M, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S, Zender L (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479 (7374):547–551. doi: 10.1038/nature10599 Google Scholar
  25. Kipling D, Jones DL, Smith SK, Giles PJ, Jennert-Burston K, Ibrahim B, Sheerin AN, Evans AJ, Rhys-Willams W, Faragher RG (2009) A transcriptomic analysis of the EK1.Br strain of human fibroblastoid keratocytes: the effects of growth, quiescence and senescence. Exp Eye Res 88(2):277–285. doi: 10.1016/j.exer.2008.11.030 PubMedCrossRefGoogle Scholar
  26. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134 (4):657–667. doi: 10.1016/j.cell.2008.06.049 Google Scholar
  27. 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(21):12072–12077. doi: 10.1073/pnas.211053698 PubMedCentralPubMedCrossRefGoogle Scholar
  28. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133 (6):1019–1031. doi: 10.1016/j.cell.2008.03.039 Google Scholar
  29. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24 (22):2463–2479. doi: 10.1101/gad.1971610 Google Scholar
  30. 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(7051):720–724PubMedCrossRefGoogle Scholar
  31. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267–273. doi: 10.1038/ng1180 PubMedCrossRefGoogle Scholar
  32. Narita M, Nunez S, Heard E, 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(6):703–716PubMedCrossRefGoogle Scholar
  33. 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(1):90–98. doi: 10.1006/excr.1994.1063 PubMedCrossRefGoogle Scholar
  34. Osorio FG, Lopez-Otin C, Freije JM (2012) NF-kB in premature aging. Aging (Albany NY) 4(11):726–727Google Scholar
  35. Riabowol KT (1992) Transcription factor activity during cellular aging of human diploid fibroblasts. Biochem Cell Biol 70(10–11):1064–1072PubMedCrossRefGoogle Scholar
  36. Salama R, Sadaie M, Hoare M, Narita M (2014) Cellular senescence and its effector programs. Genes Dev 28(2):99–114. doi: 10.1101/gad.235184.113 PubMedCentralPubMedCrossRefGoogle Scholar
  37. Saretzki G, von Zglinicki T (2002) Replicative aging, telomeres, and oxidative stress. Ann N Y Acad Sci 959:24–29PubMedCrossRefGoogle Scholar
  38. 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(5):593–602PubMedCrossRefGoogle Scholar
  39. Sherr CJ, DePinho RA (2000) Cellular senescence: mitotic clock or culture shock? Cell 102(4):407–410PubMedCrossRefGoogle Scholar
  40. Shimi T, Butin-Israeli V, Adam SA, Hamanaka RB, Goldman AE, Lucas CA, Shumaker DK, Kosak ST, Chandel NS, Goldman RD (2011) The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev 25(24):2579–2593. doi: 10.1101/gad.179515.111 Google Scholar
  41. Singh T, Newman AB (2011) Inflammatory markers in population studies of aging. Ageing Res Rev 10(3):319–329. doi: 10.1016/j.arr.2010.11.002 PubMedCentralPubMedCrossRefGoogle Scholar
  42. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550. doi: 10.1073/pnas.0506580102 PubMedCentralPubMedCrossRefGoogle Scholar
  43. Suram A, Kaplunov J, Patel PL, Ruan H, Cerutti A, Boccardi V, Fumagalli M, Di Micco R, Mirani N, Gurung RL, Hande MP, d'Adda di Fagagna F, Herbig U (2012) Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J 31 (13):2839–2851. doi: 10.1038/emboj.2012.132
  44. Whitfield ML, George LK, Grant GD, Perou CM (2006) Common markers of proliferation. Nat Rev Cancer 6 (2):99–106. doi: 10.1038/nrc1802 Google Scholar
  45. 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(7128):656–660PubMedCrossRefGoogle Scholar
  46. Ye X, Zerlanko B, Kennedy A, Banumathy G, Zhang R, Adams PD (2007) Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Mol Cell 27(2):183–196PubMedCentralPubMedCrossRefGoogle Scholar
  47. Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, Tavare S, Arakawa S, Shimizu S, Watt FM (2009) Autophagy mediates the mitotic senescence transition. Genes Dev 23(7):798–803. doi: 10.1101/gad.519709 Google Scholar

Copyright information

© American Aging Association 2014

Authors and Affiliations

  • David M. Nelson
    • 1
    • 2
  • Tony McBryan
    • 1
    • 2
  • Jessie C. Jeyapalan
    • 3
  • John M. Sedivy
    • 3
  • Peter D. Adams
    • 1
    • 2
    Email author
  1. 1.Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
  2. 2.Beatson Institute for Cancer ResearchGlasgowUK
  3. 3.Department of Molecular Biology, Cell Biology and BiochemistryBrown UniversityProvidenceUSA

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