Skip to content


  • Commentary
  • Open Access

Irreversibility of cellular senescence: dual roles of p16INK4a/Rb-pathway in cell cycle control

Cell Division20072:10

  • Received: 28 February 2007
  • Accepted: 07 March 2007
  • Published:


The retinoblastoma (Rb) tumor suppressor gene product, pRb, has an established role in the implementation of cellular senescence, the state of irreversible G1 cell cycle arrest provoked by diverse oncogenic stresses. In murine cells, senescence cell cycle arrest can be reversed by subsequent inactivation of pRb, indicating that pRb is required not only for the onset of cellular senescence, but also for the maintenance of senescence program in murine cells. However, in human cells, once pRb is fully activated by p16INK4a, senescence cell cycle arrest becomes irreversible and is no longer revoked by subsequent inactivation of pRb, suggesting that p16INK4a/Rb-pathway activates an alternative mechanism to irreversibly block the cell cycle in human senescent cells. Here, we discuss the molecular mechanism underlying the irreversibility of senescence cell cycle arrest and its potential towards tumor suppression.


  • Reactive Oxygen Species
  • Cellular Senescence
  • Senescent Cell
  • p16INK4a Gene
  • Tumor Suppressor Gene Product


Cellular senescence is the state of stable cell cycle arrest provoked by a variety of potentially oncogenic stimuli, such as telomere shortening, DNA damage or activation of certain oncogenes [13]. Cellular senescence appears to be acting as a barrier to cancer, preventing damaged cells from undergoing aberrant proliferation [410]. Two well established tumor suppressor proteins, pRb and p53, have been shown to play key roles in cellular senescence [13]. The activities of pRb and p53 are dramatically increased during cellular senescence and inactivation of these proteins in senescent mouse embryonic fibroblasts (MEFs) results in the reversal of the senescence phenotype leading to cell cycle re-entry, suggesting that pRb and p53 are required not only for the initiation of senescence program but also for the maintenance of the senescence state in murine cells [13, 11, 12]. In human senescent cells, however, once pRb is fully engaged, particularly by its activator p16INK4a, senescence cell cycle arrest become irreversible and is no longer revoked by subsequent inactivation of pRb and p53 [1315]. Interestingly, subsequent inactivation of pRb and p53 enables human senescent cells to reinitiate DNA synthesis but fails to drive the complete cell cycle, suggesting that these cells may be arrested in G2 or M phase of the cell cycle [13, 14]. This pRb- and p53- independent cell cycle block, which seems to be specific for human cells, is likely to act as a second barrier to cellular immortalization and may help to explain the remarkable stability of the senescence cell cycle arrest in human cells [2, 15]. Recent work in our lab has uncovered an unexpected role for the p16INK4a/Rb-pathway and provided a new insight into how senescent cell cycle arrest is enforced in human cells [16]. In this commentary, we will take a closer look at the genes and mechanism involved.

The G1/S control in cellular senescence

In higher eukaryotes, pRb is a crucial gatekeeper of cell cycle progression [1721]. The activity of pRb is tightly regulated by various post-translational modifications, such as phosphorylation, acetylation and ubiquitination, and is thought to impose a block on G1 progression that is alleviated by phosphorylation [1721]. In particular, a series of cyclin-dependent kinases (CDKs), CDK2, CDK4 and CDK6, play a critical role in the phosphorylation of pRb [18, 2225]. When pRb is phosphorylated by these CDKs, pRb loses its ability to bind E2F/DP transcription factor complexes resulting in entry into S-phase of the cell cycle [2628]. However in senescent cells, the activity of CDKs is blocked by elevated expression of CDK inhibitors, p21Cip1/Waf1/Sdi1 and p16INK4a [2932]

p21Cip1/Waf1/Sdi1 is a founding member of the mammalian CDK inhibitor family and is one of the best characterized transcriptional targets of the p53 tumor suppressor protein [29, 3336]. Thus, p21Waf1/Cip1 links the p53- pathway to the Rb- pathway, providing a tight security network towards tumor suppression. Indeed, the role of p21Cip1/Waf1/Sdi1 expression is well documented in various cell culture studies; up-regulation of p21Cip1/Waf1/Sdi1 expression participates in processes such as DNA damage-induced cell cycle arrest, cellular senescence and terminal differentiation that may prevent tumor formation [22]. However, since mutations in the p21 Waf1/Cip1/Sdi1 gene are rarely observed in human cancers and mice lacking p21 Waf1/Cip1/Sdi1 gene do not exhibit any predisposition to spontaneous tumor formation [3740], it remains unclear whether p21Cip1/Waf1/Sdi1 indeed plays a key role in tumor suppression in vivo.

The INK4a gene encodes another type of CDK inhibitor, p16INK4a, which specifically binds to and inactivates D-type CDKs, CDK4 and CDK6 [41]. The binding of p16INK4a to CDK4/6 also induces redistribution of Cip/Kip family CDK inhibitors, p21Cip1/Waf1/Sdi1 and p27Kip1, from cyclinD-CDK4/6 to cyclinE-CDK2 complexes resulting in the inactivation of CDK2-kinase [22, 42, 43]. Thus, induction of p16INK4a collaborates with p21Cip1/Waf1/Sdi1 to prevent phosphorylation of pRb, leading to a stable G1 arrest in senescent cells [32]. Importantly, the p16INK4a gene is frequently inactivated in a wide range of human cancers and is therefore recognized as a tumor suppressor gene [32]. This may also be because the coding region of the p16INK4a gene is partly shared with another tumor suppressor gene called p14ARF (also called as p19ARF in mouse) [32, 44, 45]. In human cancer, however, a large number of the point mutations within this region only affect p16INK4a activity but not p14ARF activity, indicating that p16INK4a /Rb-pathway, in itself, also play key roles in tumor suppression [32].

Cytokinetic block: a second barrier in cellular senescence

Although p16INK4a is known to exert its effects through pRb, subsequent inactivation of pRb stimulates DNA synthesis but not cell proliferation if p16INK4a is ectopically expressed prior to inactivation of pRb in human cells [14]. By contrast, inactivation of pRb is sufficient to override the p16INK4a effect if pRb is inactivated prior to p16INK4a expression [14]. It is therefore likely that once pRb is fully activated by p16INK4a, pRb activates yet another mechanism that irreversibly causes cell cycle arrest either in G2 or M phase [2, 13, 14]. Indeed, a dramatic increase of poly-nucleated cells is observed when pRb and p53 were subsequently inactivated in human cells expressing high level of p16INK4a [16], suggesting that this mechanism may target cytokinesis.

To delineate the molecular events underlying this cytokinetic block in human senescent cells, we took advantages of using SVts8 cells, a conditionally immortalized human fibroblasts cell lines that express a temperature-sensitive (ts) mutant of simian virus 40 large T antigen (LT) and elevated level of endogenous telomerase [46, 47]. Using SVts8 cells, we were able to examine the irreversibility of senescence cell cycle arrest under various different conditions and have shown that p16INK4a/Rb-pathway cooperate with mitogenic signals to enforce irreversible cytokinetic block through activating production of reactive oxygen species (ROS) [16].

Although ROS are required for the physiological function of the cells, excessive ROS cause anti-proliferative effects such as apoptosis and/or cellular senescence [48]. During low stress condition, mitogenic signals inactivate pRb and therefore activate E2F/DP complexes to stimulate S-phase entry [22, 2628]. Moreover, E2F/DP activation decrease ROS levels by regulating genes involved in ROS production [16]. Thus, although mitogenic signals have the potential to stimulate ROS production, this effect appears to be counterbalanced by E2F/DP activity in proliferating normal human cells [16]. In condition of high cellular stress, however, the activity of E2F/DP is blocked by p16INK4a/Rb-pathway. In this setting, mitogenic signaling, in turn, increases the ROS production, thereby activating PKCδ, a critical downstream mediator of the ROS signaling pathway [16, 49, 50]. Importantly moreover, once, activated by ROS, PKCδ, promotes further generation of ROS, thus establishing a positive feed back loop to sustain ROS- PKCδ signaling [16]. Sustained activation of ROS- PKCδ signaling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis [5153], in human senescent cells [16]. Thus, elevated levels of p16INK4a establish an autonomous activation of ROS- PKCδ signaling, leading to an irrevocable block to cytokinesis in human senescent cells (see model in Figure 1). This system may serve as a fail-safe mechanism, especially in case of the accidental inactivation of pRb and p53 in human senescent cells [15, 16]. It is noteworthy that we were unable to see activation of PKCδ during replicative senescence in MEFs [16]. This difference may account for the reversibility of murine cell senescence.
Figure 1
Figure 1

The roles of p16INK4a /RB-pathway in senescence cell cycle arrest. In proliferating cells, the effects of mitogenic signals in ROS production are counterbalanced by E2F/DP activity. However, when E2F/DP activity is shut down by fully activated pRb, mitogenic signaling, in turn, increases the level of ROS and elicits a positive feedback activation of ROS/PKC-δ signaling pathway. Elevated levels of p16INK4a therefore establish an autonomous activation of ROS/PKC-δ signaling, leading to an irrevocable block to cytokinesis in human senescent cells.

Concluding remarks

Although we can not rule out the possibility that other mechanisms might also involved in the irreversible senescence cell cycle arrest [5459], our results reveal a novel activity of the p16INK4a/Rb- pathway and facilitate our understanding of how cellular senescence is securely controlled in human primary cells. Understanding the strict irreversibility of cellular senescence will provide valuable new insights into the development of cancer and open up new possibilities of its control [6062].



cyclin dependent kinases


the retinoblastoma tumor suppressor gene product


temperature sensitive


simian virus 40 large T antigen


mouse embryonic fibroblasts


reactive oxygen species


mitotic exit network



We thank Dr. D. Mann for helpful comments on the manuscript. We also thank members of the Hara lab for helpful discussion during the preparation of this manuscript. This work was supported by grants from Ministry of Education, Science, Sports and Technology of Japan, Ministry of Health, Labor and Welfare of Japan, and Sankyo Foundation of Life Science to E. H. A. T. is supported by the Japan Society for the Promotion of Science.

Authors’ Affiliations

Division of Protein Information, Institute for Genome Research, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan


  1. Ben-Porath I, Weinberg RA: When cells get stressed: an integrative view of cellular senescence. J Clin Invest 2004,113(1):8–13. 10.1172/JCI200420663PubMed CentralPubMedView ArticleGoogle Scholar
  2. Campisi J: Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 2005,120(4):513–522. 10.1016/j.cell.2005.02.003PubMedView ArticleGoogle Scholar
  3. Herbig U, Sedivy JM: Regulation of growth arrest in senescence: telomere damage is not the end of the story. Mech Ageing Dev 2006,127(1):16–24. 10.1016/j.mad.2005.09.002PubMedView ArticleGoogle Scholar
  4. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguria A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M: Tumour biology: senescence in premalignant tumours. Nature 2005,436(7051):642. 10.1038/436642aPubMedView ArticleGoogle Scholar
  5. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dorken B, Jenuwein T, Schmitt CA: Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 2005,436(7051):660–665. 10.1038/nature03841PubMedView ArticleGoogle Scholar
  6. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS: BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005,436(7051):720–724. 10.1038/nature03890PubMedView ArticleGoogle Scholar
  7. 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: Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005,436(7051):725–730. 10.1038/nature03918PubMed CentralPubMedView ArticleGoogle Scholar
  8. Sharpless NE, DePinho RA: Cancer: crime and punishment. Nature 2005,436(7051):636–637. 10.1038/436636aPubMedView ArticleGoogle Scholar
  9. Campisi J: Suppressing cancer: the importance of being senescent. Science 2005,309(5736):886–887. 10.1126/science.1116801PubMedView ArticleGoogle Scholar
  10. Narita M, Lowe SW: Senescence comes of age. Nat Med 2005,11(9):920–922. 10.1038/nm0905-920PubMedView ArticleGoogle Scholar
  11. Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T: Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 2003,424(6945):223–228. 10.1038/nature01764PubMedView ArticleGoogle Scholar
  12. Dirac AM, Bernards R: Reversal of senescence in mouse fibroblasts through lentiviral suppression of p53. J Biol Chem 2003,278(14):11731–11734. 10.1074/jbc.C300023200PubMedView ArticleGoogle Scholar
  13. Dai CY, Enders GH: p16 INK4a can initiate an autonomous senescence program. Oncogene 2000,19(13):1613–1622. 10.1038/sj.onc.1203438PubMedView ArticleGoogle Scholar
  14. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J: Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 2003,22(16):4212–4222. 10.1093/emboj/cdg417PubMed CentralPubMedView ArticleGoogle Scholar
  15. Ramsey MR, Sharpless NE: ROS as a tumour suppressor? Nat Cell Biol 2006,8(11):1213–1215. 10.1038/ncb1106-1213PubMedView ArticleGoogle Scholar
  16. Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H, Hara E: Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 2006,8(11):1291–1297. 10.1038/ncb1491PubMedView ArticleGoogle Scholar
  17. Sherr CJ, McCormick F: The RB and p53 pathways in cancer. Cancer Cell 2002,2(2):103–112. 10.1016/S1535-6108(02)00102-2PubMedView ArticleGoogle Scholar
  18. Cobrinik D: Pocket proteins and cell cycle control. Oncogene 2005,24(17):2796–2809. 10.1038/sj.onc.1208619PubMedView ArticleGoogle Scholar
  19. Uchida C, Miwa S, Kitagawa K, Hattori T, Isobe T, Otani S, Oda T, Sugimura H, Kamijo T, Ookawa K, Yasuda H, Kitagawa M: Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation. EMBO J 2005,24(1):160–169. 10.1038/sj.emboj.7600486PubMed CentralPubMedView ArticleGoogle Scholar
  20. Chan HM, Krstic-Demonacos M, Smith L, Demonacos C, La Thangue NB: Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Cell Biol 2001,3(7):667–674. 10.1038/35083062PubMedView ArticleGoogle Scholar
  21. Gonzalo S, Garcia-Cao M, Fraga MF, Schotta G, Peters AH, Cotter SE, Eguia R, Dean DC, Esteller M, Jenuwein T, Blasco MA: Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 2005,7(4):420–428. 10.1038/ncb1235PubMedView ArticleGoogle Scholar
  22. Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999,13(12):1501–1512.PubMedView ArticleGoogle Scholar
  23. Ciemerych MA, Sicinski P: Cell cycle in mouse development. Oncogene 2005,24(17):2877–2898. 10.1038/sj.onc.1208608PubMedView ArticleGoogle Scholar
  24. Berthet C, Klarmann KD, Hilton MB, Suh HC, Keller JR, Kiyokawa H, Kaldis P: Combined loss of Cdk2 and Cdk4 results in embryonic lethality and Rb hypophosphorylation. Dev Cell 2006,10(5):563–573. 10.1016/j.devcel.2006.03.004PubMedView ArticleGoogle Scholar
  25. Malumbres M, Barbacid M: Cell cycle kinases in cancer. Curr Opin Genet Dev 2007,17(1):60–65. 10.1016/j.gde.2006.12.008PubMedView ArticleGoogle Scholar
  26. Dimova DK, Dyson NJ: The E2F transcriptional network: old acquaintances with new faces. Oncogene 2005,24(17):2810–2826. 10.1038/sj.onc.1208612PubMedView ArticleGoogle Scholar
  27. Trimarchi JM, Lees JA: Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 2002,3(1):11–20. 10.1038/nrm714PubMedView ArticleGoogle Scholar
  28. Rowland BD, Bernards R: Re-evaluating cell-cycle regulation by E2Fs. Cell 2006,127(5):871–874. 10.1016/j.cell.2006.11.019PubMedView ArticleGoogle Scholar
  29. Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR: Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 1994,211(1):90–98. 10.1006/excr.1994.1063PubMedView ArticleGoogle Scholar
  30. Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G: Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol Cell Biol 1996,16(3):859–867.PubMed CentralPubMedView ArticleGoogle Scholar
  31. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW: Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997,88(5):593–602. 10.1016/S0092-8674(00)81902-9PubMedView ArticleGoogle Scholar
  32. Gil J, Peters G: Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 2006,7(9):667–677. 10.1038/nrm1987PubMedView ArticleGoogle Scholar
  33. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B: WAF1, a potential mediator of p53 tumor suppression. Cell 1993,75(4):817–825. 10.1016/0092-8674(93)90500-PPubMedView ArticleGoogle Scholar
  34. Gu Y, Turck CW, Morgan DO: Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature 1993,366(6456):707–710. 10.1038/366707a0PubMedView ArticleGoogle Scholar
  35. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ: The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993,75(4):805–816. 10.1016/0092-8674(93)90499-GPubMedView ArticleGoogle Scholar
  36. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D: p21 is a universal inhibitor of cyclin kinases. Nature 1993,366(6456):701–704. 10.1038/366701a0PubMedView ArticleGoogle Scholar
  37. El-Deiry WS: p21/p53, cellular growth control and genomic integrity. Curr Top Microbiol Immunol 1998, 227: 121–137.PubMedGoogle Scholar
  38. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P: Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 1995,82(4):675–684. 10.1016/0092-8674(95)90039-XPubMedView ArticleGoogle Scholar
  39. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ: Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 1995,377(6549):552–557. 10.1038/377552a0PubMedView ArticleGoogle Scholar
  40. Pantoja C, Serrano M: Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras. Oncogene 1999,18(35):4974–4982. 10.1038/sj.onc.1202880PubMedView ArticleGoogle Scholar
  41. Serrano M, Hannon GJ, Beach D: A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993,366(6456):704–707. 10.1038/366704a0PubMedView ArticleGoogle Scholar
  42. McConnell BB, Gregory FJ, Stott FJ, Hara E, Peters G: Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes. Mol Cell Biol 1999,19(3):1981–1989.PubMed CentralPubMedView ArticleGoogle Scholar
  43. Mitra J, Dai CY, Somasundaram K, El-Deiry WS, Satyamoorthy K, Herlyn M, Enders GH: Induction of p21(WAF1/CIP1) and inhibition of Cdk2 mediated by the tumor suppressor p16(INK4a). Mol Cell Biol 1999,19(5):3916–3928.PubMed CentralPubMedView ArticleGoogle Scholar
  44. Quelle DE, Zindy F, Ashmun RA, Sherr CJ: Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995,83(6):993–1000. 10.1016/0092-8674(95)90214-7PubMedView ArticleGoogle Scholar
  45. Sherr CJ: Divorcing ARF and p53: an unsettled case. Nat Rev Cancer 2006,6(9):663–673. 10.1038/nrc1954PubMedView ArticleGoogle Scholar
  46. Tsuyama N, Miura M, Kitahira M, Ishibashi S, Ide T: SV40 T-antigen is required for maintenance of immortal growth in SV40-transformed human fibroblasts. Cell Struct Funct 1991,16(1):55–62.PubMedView ArticleGoogle Scholar
  47. Tahara H, Sato E, Noda A, Ide T: Increase in expression level of p21sdi1/cip1/waf1 with increasing division age in both normal and SV40-transformed human fibroblasts. Oncogene 1995,10(5):835–840.PubMedGoogle Scholar
  48. Finkel T: Oxidant signals and oxidative stress. Curr Opin Cell Biol 2003,15(2):247–254. 10.1016/S0955-0674(03)00002-4PubMedView ArticleGoogle Scholar
  49. Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, Kikkawa U, Nishizuka Y: Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc Natl Acad Sci USA 1997,94(21):11233–11237. 10.1073/pnas.94.21.11233PubMed CentralPubMedView ArticleGoogle Scholar
  50. Wheaton K, Riabowol K: Protein kinase C delta blocks immediate-early gene expression in senescent cells by inactivating serum response factor. Mol Cell Biol 2004,24(16):7298–7311. 10.1128/MCB.24.16.7298-7311.2004PubMed CentralPubMedView ArticleGoogle Scholar
  51. Iida S, Hirota T, Morisaki T, Marumoto T, Hara T, Kuninaka S, Honda S, Kosai K, Kawasuji M, Pallas DC, Saya H: Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function. Oncogene 2004,23(31):5266–5274. 10.1038/sj.onc.1207623PubMedView ArticleGoogle Scholar
  52. Yang X, Yu K, Hao Y, Li DM, Stewart R, Insogna KL, Xu T: LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1. Nat Cell Biol 2004,6(7):609–617. 10.1038/ncb1140PubMedView ArticleGoogle Scholar
  53. Bothos J, Tuttle RL, Ottey M, Luca FC, Halazonetis TD: Human LATS1 is a mitotic exit network kinase. Cancer Res 2005,65(15):6568–6575. 10.1158/0008-5472.CAN-05-0862PubMedView ArticleGoogle Scholar
  54. Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW: Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003,113(6):703–716. 10.1016/S0092-8674(03)00401-XPubMedView ArticleGoogle Scholar
  55. Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD: Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 2005,8(1):19–30. 10.1016/j.devcel.2004.10.019PubMedView ArticleGoogle Scholar
  56. Narita M, Narita M, Krizhanovsky V, Nunez S, Chicas A, Hearn SA, Myers MP, Lowe SW: A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 2006,126(3):503–514. 10.1016/j.cell.2006.05.052PubMedView ArticleGoogle Scholar
  57. Funayama R, Saito M, Tanobe H, Ishikawa F: Loss of linker histone H1 in cellular senescence. J Cell Biol 2006,175(6):869–880. 10.1083/jcb.200604005PubMed CentralPubMedView ArticleGoogle Scholar
  58. Chang BD, Broude EV, Fang J, Kalinichenko TV, Abdryashitov R, Poole JC, Roninson IB: p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 2000,19(17):2165–2170. 10.1038/sj.onc.1203573PubMedView ArticleGoogle Scholar
  59. Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski K: A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 2006,10(6):459–472. 10.1016/j.ccr.2006.10.003PubMed CentralPubMedView ArticleGoogle Scholar
  60. Shay JW, Roninson IB: Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 2004,23(16):2919–2933. 10.1038/sj.onc.1207518PubMedView ArticleGoogle Scholar
  61. Dimri GP: What has senescence got to do with cancer? Cancer Cell 2005,7(6):505–512. 10.1016/j.ccr.2005.05.025PubMed CentralPubMedView ArticleGoogle Scholar
  62. Schmitt CA: Cellular senescence and cancer treatment. Biochim Biophys Acta 2007,1775(1):5–20.PubMedGoogle Scholar


© Takahashi et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.