Cellular senescence: when bad things happen to good cells (original) (raw)
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res.37, 614–636 (1965). A classic paper that describes the limited replicative lifespan of normal human cells. CASPubMed Google Scholar
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell100, 57–70 (2000). CASPubMed Google Scholar
Bishop, J. M. Cancer: the rise of the genetic paradigm. Genes Dev.9, 1309–1315 (1995). References 2 and 3 describe the characteristics of cancer cells and the importance of mutations in cancer development. CASPubMed Google Scholar
Busuttil, R. A., Rubio, M., Dolle, M. E., Campisi, J. & Vijg, J. Mutant frequencies and spectra depend on growth state and passage number in cells cultured from transgenic _lacZ_-plasmid reporter mice. DNA Repair5, 52–60 (2006). CASPubMed Google Scholar
Campisi, J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol.11, 27–31 (2001). Google Scholar
Braig, M. & Schmitt, C. A. Oncogene-induced senescence: putting the brakes on tumor development. Cancer Res.66, 2881–2884 (2006). CASPubMed Google Scholar
Campisi, J. Cancer and ageing: rival demons? Nature Rev. Cancer3, 339–349 (2003). CAS Google Scholar
Kirkwood, T. B. & Austad, S. N. Why do we age? Nature408, 233–238 (2000). CASPubMed Google Scholar
Wright, W. E. & Shay, J. W. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr. Opin. Genet. Dev.11, 98–103 (2001). CASPubMed Google Scholar
Campisi, J. Senescent cells, tumor suppression and organismal aging: good citizens, bad neighbors. Cell120, 513–522 (2005). CASPubMed Google Scholar
Hornsby, P. J. Cellular senescence and tissue aging in vivo. J. Gerontol.57, 251–256 (2002). References 5–13 describe the historic and current evidence that cellular senescence suppresses the development of cancer. In addition, references 8 and 9 explain the concept of antagonistic pleiotropy. Google Scholar
Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell127, 265–275 (2006). CASPubMed Google Scholar
DiLeonardo, A., Linke, S. P., Clarkin, K. & Wahl, G. M. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev.8, 2540–2551 (1994). CAS Google Scholar
Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell14, 501–513 (2004). CASPubMed Google Scholar
Ogryzko, V. V., Hirai, T. H., Russanova, V. R., Barbie, D. A. & Howard, B. H. Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol. Cell. Biol.16, 5210–5218 (1996). CASPubMedPubMed Central Google Scholar
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell88, 593–602 (1997). ArticleCASPubMed Google Scholar
Wada, T. et al. MKK7 couples stress signaling to G2/M cell-cycle progression and cellular senescence. Nature Cell Biol.6, 215–226 (2004). CASPubMed Google Scholar
Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature444, 638–642 (2006). CASPubMed Google Scholar
Olsen, C. L., Gardie, B., Yaswen, P. & Stampfer, M. R. Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion. Oncogene21, 6328–6339 (2002). CASPubMed Google Scholar
Zhu, J., Woods, D., McMahon, M. & Bishop, J. M. Senescence of human fibroblasts induced by oncogenic raf. Genes Dev.12, 2997–3007 (1998). CASPubMedPubMed Central Google Scholar
Shay, J. W. & Roninson, I. B. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene23, 2919–2933 (2004). References 15–23 show that many potentially oncogenic stimuli can induce a senescence response. CASPubMed Google Scholar
Itahana, K., Campisi, J. & Dimri, G. P. Mechanisms of cellular senescence in human and mouse cells. Biogerontology5, 1–10 (2004). CASPubMed Google Scholar
Ellis, R. E., Yuan, J. Y. & Horvitz, H. R. Mechanisms and functions of cell death. Annu. Rev. Cell Biol.7, 663–698 (1991). CASPubMed Google Scholar
Green, D. R. & Evan, G. I. A matter of life and death. Cancer Cell1, 19–30 (2002). CASPubMed Google Scholar
Hampel, B., Malisan, F., Niederegger, H., Testi, R. & Jansen-Durr, P. Differential regulation of apoptotic cell death in senescent human cells. Exp. Gerontol.39, 1713–1721 (2004). CASPubMed Google Scholar
Chen, Q. M., Liu, J. & Merrett, J. B. Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts. Biochem. J.347, 543–551 (2000). CASPubMedPubMed Central Google Scholar
Tepper, C. G., Seldin, M. F. & Mudryj, M. Fas-mediated apoptosis of proliferating, transiently growth-arrested, and senescent normal human fibroblasts. Exp. Cell Res.260, 9–19 (2000). CASPubMed Google Scholar
Rebbaa, A., Zheng, X., Chou, P. M. & Mirkin, B. L. Caspase inhibition switches doxorubicin-induced apoptosis to senescence. Oncogene22, 2805–2811 (2003). CASPubMed Google Scholar
Seluanov, A. et al. Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53. Mol. Cell. Biol.21, 1552–1564 (2001). CASPubMedPubMed Central Google Scholar
Crescenzi, E., Palumbo, G. & Brady, H. J. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem. J.375, 263–274 (2003). CASPubMedPubMed Central Google Scholar
Marcotte, R., Lacelle, C. & Wang, E. Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech. Ageing Dev.125, 777–783 (2004). CASPubMed Google Scholar
Murata, Y. et al. Death-associated protein 3 regulates cellular senescence through oxidative stress response. FEBS Lett.580, 6093–6099 (2006). CASPubMed Google Scholar
Jackson, J. G. & Pereira-Smith, O. M. p53 is preferentially recruited to the promoters of growth arrest genes p21 and GADD45 during replicative senescence of normal human fibroblasts. Cancer Res.66, 8356–8360 (2006). CASPubMed Google Scholar
Chang, B. D. et al. Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc. Natl Acad. Sci. USA99, 389–394 (2002). CASPubMed Google Scholar
Mason, D. X., Jackson, T. J. & Lin, A. W. Molecular signature of oncogenic ras-induced senescence. Oncogene23, 9238–9246 (2004). CASPubMed Google Scholar
Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. & Funk, W. D. Microarray analysis of replicative senescence. Curr. Biol.9, 939–945 (1999). CASPubMed Google Scholar
Trougakos, I. P., Saridaki, A., Panayotou, G. & Gonos, E. S. Identification of differentially expressed proteins in senescent human embryonic fibroblasts. Mech. Ageing Dev.127, 88–92 (2006). CASPubMed Google Scholar
Yoon, I. K. et al. Exploration of replicative senescence-associated genes in human dermal fibroblasts by cDNA microarray technology. Exp. Gerontol.39, 1369–1378 (2004). CASPubMed Google Scholar
Zhang, H., Pan, K. H. & Cohen, S. N. Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci. Proc. Natl Acad. Sci. USA100, 3251–3256 (2003). References 36–41 describe the many changes in gene expression that are linked to the senescence response. CASPubMedPubMed Central Google Scholar
Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell2, 103–112 (2002). CASPubMed Google Scholar
Espinosa, J. M., Verdun, R. E. & Emerson, B. M. p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage. Mol. Cell12, 1015–1027 (2003). CASPubMed Google Scholar
Gil, J. & Peters, G. Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all. Nature Rev. Mol. Cell Biol.7, 667–677 (2006). CAS Google Scholar
Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell113, 703–716 (2003). The first description of senescence-associated heterochromatin foci. CASPubMed Google Scholar
Pang, J. H. & Chen, K. Y. Global change of gene expression at late G1/S boundary may occur in human IMR-90 diploid fibroblasts during senescence. J. Cell Physiol.160, 531–538 (1994). CASPubMed Google Scholar
Seshadri, T. & Campisi, J. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science247, 205–209 (1990). CASPubMed Google Scholar
Stein, G. H., Drullinger, L. F., Robetorye, R. S., Pereira-Smith, O. M. & Smith, J. R. Senescent cells fail to express CDC2, CYCA, and CYCB in response to mitogen stimulation. Proc. Natl Acad. Sci USA88, 11012–11016 (1991). CASPubMedPubMed Central Google Scholar
Dimri, G. P. et al. A novel biomarker identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA92, 9363–9367 (1995). First description of a senescence-associated marker that allowed the identification of senescent cellsin vivo. CASPubMedPubMed Central Google Scholar
Lee, B. Y. et al. Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell5, 187–195 (2006). CASPubMed Google Scholar
Beausejour, C. M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J.22, 4212–4222 (2003). CASPubMedPubMed Central Google Scholar
Itahana, K. et al. Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol. Cell. Biol.23, 389–401 (2003). CASPubMedPubMed Central Google Scholar
Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nature Rev. Cancer6, 472–476 (2006). CAS Google Scholar
d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature426, 194–198 (2003). CASPubMed Google Scholar
Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol.13, 1549–1556 (2003). References 55 and 56, along with reference 16, provide the first direct evidence that dysfunctional telomeres trigger a DNA-damage response. CASPubMed Google Scholar
Bartholdi, M. F. Nuclear distribution of centromeres during the cell cycle of human diploid fibroblasts. J. Cell Sci.99, 255–263 (1991). PubMed Google Scholar
Cerda, M. C., Berrios, S., Fernandez-Donoso, R., Garagna, S. & Redi, C. Organisation of complex nuclear domains in somatic mouse cells. Biol. Cell91, 55–65 (1999). CASPubMed Google Scholar
d'Adda di Fagagna, F., Teo, S. H. & Jackson, S. P. Functional links between telomeres and proteins of the DNA-damage response. Genes Dev.18, 1781–1799 (2004). PubMed Google Scholar
Griffith, J. D. et al. Mammalian telomeres end in a large duplex loop. Cell97, 503–514 (1999). CASPubMed Google Scholar
Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during aging of human fibroblasts. Nature345, 458–460 (1990). First evidence linking telomere shortening to replicative senescence. CASPubMed Google Scholar
Hemann, M. T., Strong, M.A., Hao, L. Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell107, 67–77 (2001). CASPubMed Google Scholar
Martens, U. M., Chavez, E. A., Poon, S. S., Schmoor, C. & Lansdorp, P. M. Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp. Cell Res.256, 291–299 (2000). CASPubMed Google Scholar
Gire, V., Roux, P., Wynford-Thomas, D., Brondello, J. M. & Dulic, V. DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J.23, 2554–2563 (2004). CASPubMedPubMed Central Google Scholar
Collins, K. & Mitchell, J. R. Telomerase in the human organism. Oncogene21, 564–579 (2002). CASPubMed Google Scholar
Effros, R. B., Dagarag, M. & Valenzuela, H. F. In vitro senescence of immune cells. Exp. Gerontol.38, 1243–1249 (2003). CASPubMed Google Scholar
Masutomi, K. et al. Telomerase maintains telomere structure in normal human cells. Cell114, 241–253 (2003). CASPubMed Google Scholar
Bodnar, A. G. et al. Extension of life span by introduction of telomerase into normal human cells. Science279, 349–352 (1998). CASPubMed Google Scholar
Chen, Q. M., Prowse, K. R., Tu, V. C., Purdom, S. & Linskens, M. H. Uncoupling the senescent phenotype from telomere shortening in hydrogen peroxide-treated fibroblasts. Exp. Cell Res.265, 294–303 (2001). CASPubMed Google Scholar
Parrinello, S. et al. Oxygen sensitivity severely limits the replicative life span of murine cells. Nature Cell Biol.5, 741–747 (2003). CASPubMed Google Scholar
Jacobs, J. J. & de Lange, T. Significant role for p16(INK4a) in p53-independent telomere-directed senescence. Curr. Biol.14, 2302–2308 (2004). CASPubMed Google Scholar
Stein, G. H., Drullinger, L. F., Soulard, A. & Dulic, V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell. Biol.19, 2109–2117 (1999). CASPubMedPubMed Central Google Scholar
Roninson, I. B. Tumor cell senescence in cancer treatment. Cancer Res.63, 2705–2715 (2003). CASPubMed Google Scholar
Roberson, R. S., Kussick, S. J., Vallieres, E., Chen, S. Y. & Wu, D. Y. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res.65, 2795–2803 (2005). CASPubMed Google Scholar
Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell109, 335–346 (2002). CASPubMed Google Scholar
te Poele, R. H., Okorokov, A. L., Jardine, L., Cummings, J. & Joel, S. P. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res.62, 1876–1883 (2002). References 73–76 describe evidence that tumour cells can undergo senescence in response to DNA-damaging chemotherapy. CASPubMed Google Scholar
Munro, J., Barr, N. I., Ireland, H., Morrison, V. & Parkinson, E. K. Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock. Exp. Cell Res.295, 525–538 (2004). CASPubMed Google Scholar
Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature421, 499–506 (2003). CASPubMed Google Scholar
Bandyopadhyay, D. et al. Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes. Cancer Res.62, 6231–6239 (2002). CASPubMed Google Scholar
Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev. Cancer6, 38–51 (2006). CAS Google Scholar
Dimri, G. P., Itahana, K., Acosta, M. & Campisi, J. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14/ARF tumor suppressor. Mol. Cell. Biol.20, 273–285 (2000). CASPubMedPubMed Central Google Scholar
Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev.12, 3008–3019 (1998). CASPubMedPubMed Central Google Scholar
Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human nevi. Nature436, 720–724 (2005). CASPubMed Google Scholar
Woo, R. A. & Poon, R. Y. Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation. Genes Dev.18 (2004).
Mathon, N. F., Malcolm, D. S., Harrisingh, M. C., Cheng, L. & Lloyd, A. C. Lack of replicative senescence in normal rodent glia. Science291, 872–875 (2001). CASPubMed Google Scholar
Tang, D. G., Tokumoto, Y. M., Apperly, J. A., Lloyd, A. C. & Raff, M. C. Lack of replicative senescence in cultured rat oligodendrocyte precursor cells. Science291, 868–871 (2001). CASPubMed Google Scholar
Ohtani, N. et al. Opposing effects of Ets and Id proteins on p16/INK4a expression during cellular senescence. Nature409, 1067–1070 (2001). CASPubMed Google Scholar
Zhang, R. et al. Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell8, 19–31 (2005). CASPubMed Google Scholar
Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature444, 633–637 (2006). CASPubMed Google Scholar
Benanti, J. A. & Galloway, D. A. Normal human fibroblasts are resistant to RAS-induced senescence. Mol. Cell. Biol.24, 2842–2852 (2004). CASPubMedPubMed Central Google Scholar
Skinner, J. et al. Opposing effects of mutant ras oncoprotein on human fibroblast and epithelial cell proliferation: implications for models of human tumorigenesis. Oncogene23, 5994–5999 (2004). CASPubMed Google Scholar
Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature436, 660–665 (2005). CASPubMed Google Scholar
Chen, Z. et al. Critical role of p53-dependent cellular senescence in suppression of PTEN-deficient tumorigenesis. Nature436, 725–730 (2005). CASPubMedPubMed Central Google Scholar
Collado, M. et al. Identification of senescent cells in premalignant tumours. Nature436, 642 (2005). CASPubMed Google Scholar
Lazzerini Denchi, E., Attwooll, C., Pasini, D. & Helin, K. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol. Cell. Biol.25, 2660–2672 (2005). Together with references 83 and 89, references 92–95 provide evidence that cellular senescence suppresses tumorigenesisin vivo. PubMed Google Scholar
Moiseeva, O., Mallette, F. A., Mukhopadhyay, U. K., Moores, A. & Ferbeyre, G. DNA damage signaling and p53-dependent senescence after prolonged β-interferon stimulation. Mol. Biol. Cell17, 1583–1592 (2006). CASPubMedPubMed Central Google Scholar
Vijayachandra, K., Lee, J. & Glick, A. B. Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model. Cancer Res.63, 3447–3452 (2003). CASPubMed Google Scholar
Zhang, H. & Cohen, S. N. Smurf2 up-regulation activates telomere-dependent senescence. Genes Dev.18, 3028–3040 (2004). CASPubMedPubMed Central Google Scholar
Ramirez, R. D. et al. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev.15, 398–403 (2001). CASPubMedPubMed Central Google Scholar
Brenner, A. J., Stampfer, M. R. & Aldaz, C. M. Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene17, 199–205 (1998). CASPubMed Google Scholar
Huschtscha, L. I. et al. Loss of p16INK4 expression by methylation is associated with lifespan extension of human mammary epithelial cells. Cancer Res.58, 3508–3512 (1998). CASPubMed Google Scholar
Forsyth, N. R., Evans, A. P., Shay, J. W. & Wright, W. E. Developmental differences in the immortalization of lung fibroblasts by telomerase. Aging Cell2, 235–243 (2003). CASPubMed Google Scholar
Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene BMI-1 regulates cell proliferation and senescence through the INK4a locus. Nature397, 164–168 (1999). CASPubMed Google Scholar
Zindy, F., Quelle, D. E., Roussel, M. F. & Sherr, C. J. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene15, 203–211 (1997). First report that p16 expression increases during ageing. CASPubMed Google Scholar
Janzen, V. et al. Stem cell aging modified by the cyclin-dependent kinase inhibitor, p16INK4a. Nature443, 421–426 (2006). CASPubMed Google Scholar
Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature443, 453–457 (2006). CASPubMed Google Scholar
Molofsky, A. V. et al. Declines in forebrain progenitor function and neurogenesis during aging are partially caused by increasing Ink4a expression. Nature443, 448–452 (2006). References 105–107 describe evidence that p16 limits stem-cell or progenitor-cell proliferation, which drives ageing phenotypes. CASPubMedPubMed Central Google Scholar
Holst, C. R. et al. Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res.63, 1596–1601 (2003). CASPubMed Google Scholar
Brown, J. P., Wei, W. & Sedivy, J. M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science277, 831–834 (1997). CASPubMed Google Scholar
Won, J. et al. Small molecule-based reversible reprogramming of cellular lifespan. Nature Chem. Biol.2, 369–374 (2006). CAS Google Scholar
Shay, J. W. & Wright, W. E. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis26, 867–874 (2005). CASPubMed Google Scholar
Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature434, 864–870 (2005). CASPubMed Google Scholar
Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature434, 907–913 (2005). CASPubMed Google Scholar
Smogorzewska, A. & de Lange, T. Different telomere damage signaling pathways in human and mouse cells. EMBO J.21, 4338–4348 (2002). CASPubMedPubMed Central Google Scholar
Hara, E. et al. Id related genes encoding helix loop helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J. Biol. Chem.269, 2139–2145 (1994). CASPubMed Google Scholar
Bracken, A. P. et al. The Polycomb group proteins bind throughout the INK4A–ARF locus and are disassociated in senescent cells. Genes Dev.21, 525–530 (2007). CASPubMedPubMed Central Google Scholar
Gil, J., Bernard, D., Martinez, D. & Beach, D. Polycomb CBX7 has a unifying role in cellular lifespan. Nature Cell Biol.6, 62–67 (2004). Google Scholar
Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev.13, 1501–1512 (1999). CASPubMed Google Scholar
Bates, S. et al. p14ARF links the tumor suppressors RB and p53. Nature395, 125–125 (1998). Google Scholar
Zhang, J., Pickering, C. R., Holst, C. R., Gauthier, M. L. & Tlsty, T. D. p16INK4a modulates p53 in primary human mammary epithelial cells. Cancer Res.66, 10325–10331 (2006). CASPubMed Google Scholar
Funayama, R., Saito, M., Tanobe, H. & Ishikawa, F. Loss of linker histone H1 in cellular senescence. J. Cell Biol.175, 869–880 (2006). CASPubMedPubMed Central Google Scholar
Zhang, R., Chen, W. & Adams, P. D. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol. Cell. Biol.27, 2343–2358 (2007). CASPubMedPubMed Central Google Scholar
Macaluso, M., Montanari, M. & Giordano, A. Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes. Oncogene25, 5263–5267 (2006). CASPubMed Google Scholar
Jeyapalan, J. C., Ferreira, M., Sedivy, J. M. & Herbig, U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev.128, 36–44 (2007). CASPubMed Google Scholar
Chang, E. & Harley, C. B. Telomere length and replicative aging in human vascular tissues. Proc. Natl Acad. Sci. USA92, 11190–11194 (1995). CASPubMedPubMed Central Google Scholar
Price, J. S. et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell1, 57–65 (2002). CASPubMed Google Scholar
Vasile, E., Tomita, Y., Brown, L. F., Kocher, O. & Dvorak, H. F. Differential expression of thymosin β-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, 458–466 (2001). CASPubMed Google Scholar
Castro, P., Giri, D., Lamb, D. & Ittmann, M. Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate55, 30–38 (2003). CASPubMed Google Scholar
Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature445, 661–665 (2007). CASPubMed Google Scholar
Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature445, 656–650 (2007). CASPubMedPubMed Central Google Scholar
Cosme-Blanco, W. et al. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep.8, 497–503 (2007). CASPubMedPubMed Central Google Scholar
Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B. & Evan, G. I. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature443, 214–217 (2006). CASPubMed Google Scholar
Feldser, D. M. & Greider, C. W. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell11, 461–469 (2007). CASPubMedPubMed Central Google Scholar
Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature356, 215–221 (1992). CASPubMed Google Scholar
Iwakuma, T., Lozano, G. & Flores, E. R. Li-Fraumeni syndrome: a p53 family affair. Cell Cycle4, 865–867 (2005). CASPubMed Google Scholar
Lee, S. B. et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni syndrome. Cancer Res.61, 8062–8067 (2001). CASPubMed Google Scholar
Shay, J. W., Tomlinson, G., Piatyszek, M. A. & Gollahon, L. S. Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. Mol. Cell Biol.15, 425–432 (1995). CASPubMedPubMed Central Google Scholar
Morales, C. P. et al. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nature Genet.21, 115–118 (1999). CASPubMed Google Scholar
Shay, J. W., Van Der Haegen, B. A., Ying, Y. & Wright, W. E. The frequency of immortalization of human fibroblasts and mammary epithelial cells transfected with SV40 large T-antigen. Exp. Cell Res.209, 45–52 (1993). CASPubMed Google Scholar
Hahn, W. C. et al. Creation of human tumor cells with defined genetic elements. Nature400, 464–468 (1999). CASPubMed Google Scholar
Tyner, S. D. et al. p53 mutant mice that display early aging-associated phenotypes. Nature415, 45–53 (2002). CASPubMed Google Scholar
Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev.18, 306–319 (2004). References 141 and 142 show that constitutive p53 activity can suppress the development of cancer at the cost of accelerating ageing phenotypes. CASPubMedPubMed Central Google Scholar
Funk, W. D. et al. Telomerase expression restores dermal integrity to in vitro aged fibroblasts in a reconstituted skin model. Exp. Cell Res.258, 270–278 (2000). CASPubMed Google Scholar
Parrinello, S., Coppe, J. P., Krtolica, A. & Campisi, J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci.118, 485–496 (2005). CASPubMed Google Scholar
Bavik, C. et al. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res.66, 794–802 (2006). CASPubMed Google Scholar
Coppe, J. P., Kauser, K., Campisi, J. & Beausejour, C. M. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem.281, 29568–29574 (2006). CASPubMed Google Scholar
Dilley, T. K., Bowden, G. T. & Chen, Q. M. Novel mechanisms of sublethal oxidant toxicity: induction of premature senescence in human fibroblasts confers tumor promoter activity. Exp. Cell Res.290, 38–48 (2003). CASPubMed Google Scholar
Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA98, 12072–12077 (2001). CASPubMedPubMed Central Google Scholar
Martens, J. W. et al. Aging of stromal-derived human breast fibroblasts might contribute to breast cancer progression. Thromb. Haemost.89, 393–404 (2003). CASPubMed Google Scholar
Garcia-Cao, I. et al. 'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J.21, 6225–6235 (2002). CASPubMedPubMed Central Google Scholar
Matheu, A. et al. Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging. Genes Dev.18, 2736–2746 (2004). CASPubMedPubMed Central Google Scholar
Mendrysa, S. M. et al. Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev.20, 16–21 (2006). References 150–152 show that resistance to cancer need not accelerate ageing. CASPubMedPubMed Central Google Scholar
Shay, J. W., Wright, W. E. & Werbin, H. Defining the molecular mechanisms of human cell immortalization. Biochim. Biophys. Acta Rev. Cancer1071, 1–7 (1991). Google Scholar
Romanov, S. R. et al. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature409, 633–637 (2001). CASPubMed Google Scholar
Emsley, J. G., Mitchell, B. D., Kempermann, G. & Macklis, J. D. Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog. Neurobiol.75, 321–341 (2005). CASPubMed Google Scholar
Shi, X. & Garry, D. J. Muscle stem cells in development, regeneration, and disease. Genes Dev.20, 1692–1708 (2006). CASPubMed Google Scholar
Srivastava, D. & Ivey, K. N. Potential of stem-cell-based therapies for heart disease. Nature441, 1097–1099 (2006). CASPubMed Google Scholar