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p16INK4a and Stem Cell Ageing: A Telomere-Independent Process?

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Telomeres and Telomerase in Ageing, Disease, and Cancer
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Long-lived mammals replace lost or consumed cells at a tremendous pace: an adult human replaces <1% of their many trillion red blood cells every day through de novo synthesis. Similarly, cell division at various rates is at work throughout life to continuously replace lost cells in many epithelial tissues such as the gut, skin, breast, and lung. Moreover, several tissues (e.g., memory T-lymphocytes, pancreatic β-cells) possess a potential for “facultative growth” in the adult; that is, under certain circumstances (e.g., infection, pregnancy), these usually quiescent cells re-enter the cell cycle en masse to increase the mass of a given tissue through controlled proliferation. These forms of tissue replacement and repair require that many adult mammalian tissues contain reservoirs of stem cells capable of generating terminally differentiated effector cell types. The unique cellular property that enables stem cells to maintain such function throughout life is the ability to produce large numbers of differentiated cell types while also self-renewing themselves so that their reserves do not become depleted. In this chapter, I will review some of the evidence to support the notion that certain aspects of mammalian ageing result from an age-dependent decline in the function of self-renewing stem cells, and discuss the relationship of p16INK4a and telomeres with regard to stem cell ageing.

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References

  • Ahmed S and Hodgkin J (2000) MRT-2 checkpoint protein is required for germ line immortality and telomere replication in C. elegans. Nature 403: 159–64.

    Article  PubMed  CAS  Google Scholar 

  • Akashi K, Traver D, Miyamoto T, Weissman IL (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404: 193–97.

    Article  PubMed  CAS  Google Scholar 

  • Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC (1996) Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci USA 93: 13742–47.

    Article  PubMed  CAS  Google Scholar 

  • Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, Anderson JE, Petersdorf SH (2006) Age and acute myeloid leukemia. Blood 107AA 3481–85.

    Google Scholar 

  • Ash RC, Horowitz MM, Gale RP, van Bekkum DW, Casper JT, Gordon-Smith EC, Henslee PJ, Kolb HJ, Lowenberg B, Masaoka T, et al. (1991) Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T cell depletion. Bone Marrow Tr 7: 443–52.

    CAS  Google Scholar 

  • Aslanian A, Iaquinta PJ, Verona R, Lees JA (2004) Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Genes Dev 18: 1413–22.

    Article  PubMed  CAS  Google Scholar 

  • Beghe C, Wilson A, Ershler WB (2004) Prevalence and outcomes of anemia in geriatrics: a systematic review of the literature. Am J Med 116 Suppl 7A: 3S–10S.

    Google Scholar 

  • Boccadoro M, Palumbo A, Bringhen S, Merletti F, Ciccone G, Richiardi L, Rus C, Bertola A, Giaccone L, Omede P, et al. (2002) Oral melphalan at diagnosis hampers adequate collection of peripheral blood progenitor cells in multiple myeloma. Haematologica 87, 846–50.

    PubMed  CAS  Google Scholar 

  • Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Monch K, Minucci S, Porse BT, Marine JC, et al. (2007) The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21: 525–30.

    Article  PubMed  CAS  Google Scholar 

  • Bradford GB, Williams B, Rossi R, Bertoncello I (1997) Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. Exp Hematol 25: 445–53.

    PubMed  CAS  Google Scholar 

  • Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, Jacobs JJ, Kieboom K, Tanger E, Hulsman D, Leung C, Arsenijevic Y, Marino S, et al. (2005) Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev 19: 1438–43.

    Article  PubMed  CAS  Google Scholar 

  • Brunello A, Basso U, Pogliani C, Jirillo A, Ghiotto C, Koussis H, Lumachi F, Iacobone M, Vamvakas L, Monfardini S (2005) Adjuvant chemotherapy for elderly patients (> or =70 years) with early high-risk breast cancer: a retrospective analysis of 260 patients. Ann Oncol 16: 1276–82.

    Article  PubMed  CAS  Google Scholar 

  • Bryder D, Rossi DJ, Weissman IL (2006) Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol 169, 338–46.

    Article  PubMed  CAS  Google Scholar 

  • Buckner CD, Clift RA, Sanders JE, Stewart P, Bensinger WI, Doney KC, Sullivan KM, Witherspoon RP, Deeg HJ, Appelbaum FR, et al. (1984) Marrow harvesting from normal donors. Blood 64: 630–04.

    PubMed  CAS  Google Scholar 

  • Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW, Appella E, Fornace AJ Jr (2004) Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet 36: 343–50.

    Article  PubMed  CAS  Google Scholar 

  • Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52: 102–10.

    Article  PubMed  CAS  Google Scholar 

  • Campisi J (2001) Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 11: S27–31.

    PubMed  CAS  Google Scholar 

  • Campisi J (2003) Cellular senescence and apoptosis: how cellular responses might influence ageing phenotypes. Exp Gerontol 38: 5–11.

    Article  PubMed  CAS  Google Scholar 

  • Campisi J (2005) Suppressing cancer: the importance of being senescent. Science 309: 886–87.

    Article  PubMed  CAS  Google Scholar 

  • Castro-Malaspina H, Harris RE, Gajewski J, Ramsay N, Collins R, Dharan B, King R, Deeg HJ (2002) Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 99: 1943–51.

    Article  PubMed  CAS  Google Scholar 

  • Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA (2003). Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361: 393–95.

    Article  PubMed  CAS  Google Scholar 

  • Chen J (2004) Senescence and functional failure in hematopoietic stem cells. Exp Hematol 32: 1025–32.

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Astle CM, Harrison DE (2003) Hematopoietic senescence is postponed and hematopoietic stem cell function is enhanced by dietary restriction. Exp Hematol 31:1097–1103.

    Article  PubMed  CAS  Google Scholar 

  • Cheshier SH, Morrison SJ, Liao X, Weissman IL (1999) In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci USA 96: 3120–25.

    Article  PubMed  CAS  Google Scholar 

  • Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433: 760–64.

    Article  PubMed  CAS  Google Scholar 

  • de Haan G, Nijhof W, Van Zant G (1997) Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during ageing: correlation between lifespan and cycling activity. Blood 89: 1543–50.

    PubMed  Google Scholar 

  • de Haan G, Van Zant G (1999) Dynamic changes in mouse hematopoietic stem cell numbers during ageing. Blood 93: 3294–3301.

    PubMed  Google Scholar 

  • DeGregori J, Leone G, Miron A, Jakoi L, Nevins JR (1997) Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci USA 94: 7245–50.

    Article  PubMed  CAS  Google Scholar 

  • Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH (2007) Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus. EMBO J 26: 1637–48.

    Article  PubMed  CAS  Google Scholar 

  • 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 ageing skin in vivo. Proc Natl Acad Sci USA 92: 9363–67.

    Article  PubMed  CAS  Google Scholar 

  • Dumble M, Moore L, Chambers SM, Geiger H, Van Zant G, Goodell MA, Donehower LA (2007) The impact of altered p53 dosage on hematopoietic stem cell dynamics during ageing. Blood. 109: 1736–42.

    Article  PubMed  CAS  Google Scholar 

  • Edwards MG, Anderson RM, Yuan M, Kendziorski CM, Weindruch R, Prolla TA (2007) Gene expression profiling of ageing reveals activation of a p53-mediated transcriptional program. BMC genomics 8: 80.

    Article  PubMed  CAS  Google Scholar 

  • Enomoto K, Mimura T, Harris DL, Joyce NC (2006) Age differences in cyclin-dependent kinase inhibitor expression and rb hyperphosphorylation in human corneal endothelial cells. Invest Ophthalmol Vis Sci 47: 4330–40.

    Article  PubMed  Google Scholar 

  • Enwere E, Shingo T, Gregg C, Fujikawa H, Ohta S, Weiss S (2004) Ageing results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 24: 8354–65.

    Article  PubMed  CAS  Google Scholar 

  • Foster SA, Wong DJ, Barrett MT, Galloway DA (1998) Inactivation of p16 in human mammary epithelial cells by CpG island methylation. Mol Cell Biol 18: 1793–1801.

    PubMed  CAS  Google Scholar 

  • Fried LP, Kronmal RA, Newman AB, Bild DE, Mittelmark MB, Polak JF, Robbins JA, Gardin JM (1998) Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JAMA 279: 585–92.

    Article  PubMed  CAS  Google Scholar 

  • Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, et al. (2001) Frailty in older adults: evidence for a phenotype. J Gerontol 56rrrM146–56.

    Google Scholar 

  • Gardner RV, Astle CM, Harrison DE (1997) Hematopoietic precursor cell exhaustion is a cause of proliferative defect in primitive hematopoietic stem cells (PHSC) after chemotherapy. Exp Hematol 25: 495–501.

    PubMed  CAS  Google Scholar 

  • Gil J, Bernard D, Martinez D, Beach D (2004) Polycomb CBX7 has a unifying role in cellular lifespan. Nat Cell Biol 6: 67–72.

    Article  PubMed  CAS  Google Scholar 

  • Gray-Schopfer VC, Cheong SC, Chong H, Chow J, Moss T, Abdel-Malek ZA, Marais R, Wynford-Thomas D, Bennett DC (2006) Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer 95: 496–505.

    Article  PubMed  CAS  Google Scholar 

  • Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC (2004) Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 104: 2263–68.

    Article  PubMed  CAS  Google Scholar 

  • Harrison DE (1979) Mouse erythropoietic stem cell lines function normally 100 months: loss related to number of transplantations. Mech Ageing Dev 9: 427–33.

    Article  PubMed  CAS  Google Scholar 

  • Henckaerts E, Langer JC, Snoeck HW (2004) Quantitative genetic variation in the hematopoietic stem cell and progenitor cell compartment and in lifespan are closely linked at multiple loci in BXD recombinant inbred mice. Blood 104: 374–79.

    Article  PubMed  CAS  Google Scholar 

  • Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in ageing primates. Science 311: 1257.

    Article  PubMed  CAS  Google Scholar 

  • Hodgson GS, Bradley TR (1984) In vivo kinetic status of hematopoietic stem and progenitor cells as inferred from labeling with bromodeoxyuridine. Exp Hematol 12: 683–87.

    PubMed  CAS  Google Scholar 

  • Huot TJ, Rowe J, Harland M, Drayton S, Brookes S, Gooptu C, Purkis P, Fried M, Bataille V, Hara E, et al. (2002) Biallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts. Mol Cell Biol 22: 8135–43.

    Article  PubMed  CAS  Google Scholar 

  • Huschtscha LI, Noble JR, Neumann AA, Moy EL, Barry P, Melki JR, Clark SJ, Reddel RR (1998) Loss of p16INK4 expression by methylation is associated with lifespan extension of human mammary epithelial cells. Cancer Res 58: 3508–12.

    PubMed  CAS  Google Scholar 

  • Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J, Dimri GP (2003) Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol 23: 389–401.

    Article  PubMed  CAS  Google Scholar 

  • Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, Nomiyama K, Hosokawa K, Sakurada K, Nakagata N, et al. (2004) Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431: 997–1002.

    Article  PubMed  CAS  Google Scholar 

  • Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, et al. (2006) Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12: 446–51.

    Article  PubMed  CAS  Google Scholar 

  • Jacobs JJ, de Lange T (2004) Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol 14: 2302–08.

    Article  PubMed  CAS  Google Scholar 

  • Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M (1999) The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397: 164–68.

    Article  PubMed  CAS  Google Scholar 

  • Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT (2006) Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443: 421–26.

    PubMed  CAS  Google Scholar 

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91: 649–59.

    Article  PubMed  CAS  Google Scholar 

  • Kamminga LM, Bystrykh LV, de Boer A, Houwer S, Douma J, Weersing E, Dontje B, de Haan G (2006) The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 107: 2170–79.

    Article  PubMed  CAS  Google Scholar 

  • Kim M, Moon HB, Spangrude GJ (2003) Major age-related changes of mouse hematopoietic stem/progenitor cells. Ann N Y Acad Sci 996: 195–208.

    Article  PubMed  Google Scholar 

  • Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and ageing. Cell 127: 265–75.

    Article  PubMed  CAS  Google Scholar 

  • Kitada T, Seki S, Kawakita N, Kuroki T, Monna T (1995) Telomere shortening in chronic liver diseases. Biochem Biophys Res Commun 211: 33–39.

    Article  PubMed  CAS  Google Scholar 

  • Kiyono T, Foster SA, Koop JI, McDougall JK, Galloway DA, Klingelhutz AJ (1998) Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396: 84–88.

    Article  PubMed  CAS  Google Scholar 

  • Knudsen LM, Rasmussen T, Jensen L, Johnsen HE (1999) Reduced bone marrow stem cell pool and progenitor mobilisation in multiple myeloma after melphalan treatment. Med Oncol 16: 245–54.

    Article  PubMed  CAS  Google Scholar 

  • Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH, Hegland J, Kamani N, Kernan NA, King R, et al. (2001) Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 98: 2043–51.

    Article  PubMed  CAS  Google Scholar 

  • Kondo M, Weissman IL, Akashi K (1997) Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91: 661–72.

    Article  PubMed  CAS  Google Scholar 

  • Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y (2007) pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene. Genes & development 21: 49–54.

    Article  CAS  Google Scholar 

  • Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE (2006). p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443: 453–57.

    Article  PubMed  CAS  Google Scholar 

  • Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE (2004) Ink4a/Arf expression is a biomarker of ageing. J Clin Invest 114: 1299–1307.

    PubMed  CAS  Google Scholar 

  • Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16: 2027–33.

    PubMed  CAS  Google Scholar 

  • Lang D, Lu MM, Huang L, Engleka KA, Zhang M, Chu EY, Lipner S, Skoultchi A, Millar SE, Epstein JA (2005) Pax3 functions at a nodal point in melanocyte stem cell differentiation. Nature 433: 884–87.

    Article  PubMed  CAS  Google Scholar 

  • Lenhoff S, Hjorth M, Westin J, Brinch L, Backstrom B, Carlson K, Christiansen I, Dahl IM, Gimsing P, Hammerstrom J, et al. (2006). Impact of age on survival after intensive therapy for multiple myeloma: a population-based study by the Nordic Myeloma Study Group. Br J Haematol 133: 389–96.

    Article  PubMed  Google Scholar 

  • Liang Y, Van Zant G, Szilvassy SJ (2005) Effects of ageing on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106: 1479–87.

    Article  PubMed  CAS  Google Scholar 

  • Lichtman MA, Rowe JM (2004) The relationship of patient age to the pathobiology of the clonal myeloid diseases. Semin Oncol 31: 185–97.

    Article  PubMed  Google Scholar 

  • Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5: 133–39.

    Article  PubMed  CAS  Google Scholar 

  • Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H (2004) Modulation of mammalian life span by the short isoform of p53. Genes Dev 18: 306–19.

    Article  PubMed  CAS  Google Scholar 

  • Maslov AY, Barone TA, Plunkett RJ, Pruitt SC (2004) Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci 24: 1726–33.

    Article  PubMed  CAS  Google Scholar 

  • Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, Goddard M, Bennett M (2006) Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res 99: 156–64.

    Article  PubMed  CAS  Google Scholar 

  • Meier B, Clejan I, Liu Y, Lowden M, Gartner A, Hodgkin J, Ahmed S (2006) trt-1 is the Caenorhabditis elegans catalytic subunit of telomerase. PLOS Genetics 2: e18.

    Article  PubMed  CAS  Google Scholar 

  • Melk A, Kittikowit W, Sandhu I, Halloran KM, Grimm P, Schmidt BM, Halloran PF (2003) Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 63: 2134–43.

    Article  PubMed  CAS  Google Scholar 

  • Melk A, Schmidt BM, Takeuchi O, Sawitzki B, Rayner DC, Halloran PF (2004) Expression of p16INK4a and other cell cycle regulator and senescence associated genes in ageing human kidney. Kidney Int 65: 510–20.

    Article  PubMed  CAS  Google Scholar 

  • Melzer D, Frayling TM, Murray A, Hurst AJ, Harries LW, Song H, Khaw K, Luben R, Surtees PG, Bandinelli SS (2007) A common variant of the p16(INK4a) genetic region is associated with physical function in older people. Mech Ageing Dev 128: 370–77.

    Article  PubMed  CAS  Google Scholar 

  • Meng A, Wang Y, Van Zant G, Zhou D (2003) Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. Cancer Res 63: 5414–19.

    PubMed  CAS  Google Scholar 

  • Menzel O, Migliaccio M, Goldstein DR, Dahoun S, Delorenzi M, Rufer N (2006) Mechanisms regulating the proliferative potential of human CD8+ T lymphocytes overexpressing telomerase. J Immunol 177: 3657–68.

    PubMed  CAS  Google Scholar 

  • 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: 720–24.

    Article  PubMed  CAS  Google Scholar 

  • Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402: 551–55.

    Article  PubMed  CAS  Google Scholar 

  • Miura N, Horikawa I, Nishimoto A, Ohmura H, Ito H, Hirohashi S, Shay JW, Oshimura M (1997) Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis. Cancer Genet Cytogenet 93: 56–62.

    Article  PubMed  CAS  Google Scholar 

  • Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19: 1432–37.

    Article  PubMed  CAS  Google Scholar 

  • Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425: 962–67.

    Article  PubMed  CAS  Google Scholar 

  • Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443: 448–52.

    Article  PubMed  CAS  Google Scholar 

  • Moore KA, Lemischka IR (2006) Stem cells and their niches. Science 311: 1880–85.

    Article  PubMed  CAS  Google Scholar 

  • Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL (1996) The ageing of hematopoietic stem cells. Nat Med 2: 1011–16.

    Article  PubMed  CAS  Google Scholar 

  • 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: 703–16.

    Article  PubMed  CAS  Google Scholar 

  • Nielsen GP, Stemmer-Rachamimov AO, Shaw J, Roy JE, Koh J, Louis DN (1999) Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. Lab Invest 79: 1137–43.

    PubMed  CAS  Google Scholar 

  • Nishimura EK, Granter SR, Fisher DE (2005) Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307: 720–24.

    Article  PubMed  CAS  Google Scholar 

  • Obana N, Takagi S, Kinouchi Y, Tokita Y, Sekikawa A, Takahashi S, Hiwatashi N, Oikawa S, Shimosegawa T (2003) Telomere shortening of peripheral blood mononuclear cells in coronary disease patients with metabolic disorders. Intern Med 42: 150–53.

    Article  PubMed  CAS  Google Scholar 

  • Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H (2006) Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med 203: 2247–53.

    Article  PubMed  CAS  Google Scholar 

  • Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E (2001) Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409: 1067–70.

    Article  PubMed  CAS  Google Scholar 

  • Osawa M, Hanada K, Hamada H, Nakauchi H (1996) Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273: 242–45.

    Article  PubMed  CAS  Google Scholar 

  • Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ, Clarke MF (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423: 302–05.

    Article  PubMed  CAS  Google Scholar 

  • Pasini D, Bracken AP, Helin K (2004) Polycomb group proteins in cell cycle progression and cancer. Cell Cycle 3: 396–400.

    PubMed  CAS  Google Scholar 

  • Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL (2005) Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med 202: 1599–1611.

    Article  PubMed  CAS  Google Scholar 

  • Pearce DJ, Anjos-Afonso F, Ridler CM, Eddaoudi A, Bonnet D (2007) Age dependent increase in SP distribution within hematopoiesis: implications for our understanding of the mechanism of ageing. Stem Cells 25: 828–35.

    Article  PubMed  CAS  Google Scholar 

  • Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22: 44–52.

    Article  PubMed  CAS  Google Scholar 

  • Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Durr P, Wlaschek M (2006) p16INK4A is a robust in vivo biomarker of cellular ageing in human skin. Ageing Cell 5: 379–89.

    Article  CAS  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414: 105–11.

    Article  PubMed  CAS  Google Scholar 

  • Rossi DJ, Bryder D, Weissman IL (2007) Hematopoietic stem cell ageing: mechanism and consequence. Exp Gerontol 42: 385–90.

    Article  PubMed  CAS  Google Scholar 

  • Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL (2005) Cell intrinsic alterations underlie hematopoietic stem cell ageing. Proc Natl Acad Sci USA 102: 9194–99.

    Article  PubMed  CAS  Google Scholar 

  • Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T (2003) Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424: 223–28.

    Article  PubMed  CAS  Google Scholar 

  • Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH (2001) Telomere shortening in atherosclerosis. Lancet 358: 472–73.

    Article  PubMed  CAS  Google Scholar 

  • Sasaki M, Ikeda H, Sato Y, Nakanuma Y (2006) Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis. Am J Pathol 169: 831–45.

    Article  PubMed  CAS  Google Scholar 

  • Satyanarayana A, Greenberg RA, Schaetzlein S, Buer J, Masutomi K, Hahn WC, Zimmermann, S, Martens U, Manns MP, Rudolph KL (2004) Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol Cell Biol 24: 5459–74.

    Article  PubMed  CAS  Google Scholar 

  • Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316: 1331–36.

    Article  PubMed  CAS  Google Scholar 

  • Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4dd 7–25.

    Google Scholar 

  • Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316: 1341–45.

    Article  PubMed  CAS  Google Scholar 

  • Sharpless NE (2005) INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res 576: 22–38.

    PubMed  CAS  Google Scholar 

  • Sone H, Kagawa Y (2005) Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48: 58–67.

    Article  PubMed  CAS  Google Scholar 

  • Sparmann A, van Lohuizen M (2006. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6: 846–56.

    Article  PubMed  CAS  Google Scholar 

  • Stein GH, Drullinger LF, Soulard A, Dulic V (1999) Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol 19: 2109–17.

    PubMed  CAS  Google Scholar 

  • Stepanova L, Sorrentino BP (2005) A limited role for p16Ink4a and p19Arf in the loss of hematopoietic stem cells during proliferative stress. Blood 106: 827–32.

    Article  PubMed  CAS  Google Scholar 

  • Sudo K, Ema H, Morita Y, Nakauchi H (2000) Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 192: 1273–80.

    Article  PubMed  CAS  Google Scholar 

  • TeKippe M, Harrison DE, Chen J (2003) Expansion of hematopoietic stem cell phenotype and activity in Trp53-null mice. Exp Hematol 31EE 521–27.

    Google Scholar 

  • Tsuji T, Aoshiba K, Nagai A (2006) Alveolar cell senescence in patients with pulmonary emphysema. Am J Respir Crit Care Med 174: 886–93.

    Article  PubMed  CAS  Google Scholar 

  • Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H (1999) Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Mol Cell Biol 19: 7011–19.

    PubMed  CAS  Google Scholar 

  • Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, et al. (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature 415: 45–53.

    Article  PubMed  CAS  Google Scholar 

  • Urabe Y, Nouso K, Higashi T, Nakatsukasa H, Hino N, Ashida K, Kinugasa N, Yoshida K, Uematsu S, Tsuji T (1996) Telomere length in human liver diseases. Liver 16: 293–97.

    Article  PubMed  CAS  Google Scholar 

  • Urbanek K, Torella D, Sheikh F, De Angelis A, Nurzynska D, Silvestri F, Beltrami CA, Bussani R, Beltrami AP, Quaini F, et al. (2005) Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci USA 102: 8692–97.

    Article  PubMed  CAS  Google Scholar 

  • von Zglinicki T, Saretzki G, Ladhoff J, d’Adda di Fagagna F, Jackson SP (2005) Human cell senescence as a DNA damage response. Mech Ageing Dev 126: 111–17.

    Article  CAS  Google Scholar 

  • Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I (2001) The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413: 432–35.

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S, Sun P (2002) Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6–p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol 22: 3389–3403.

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Schulte BA, Larue AC, Ogawa M, Zhou D (2006) Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood 107: 358–66.

    Article  PubMed  CAS  Google Scholar 

  • Weissman IL (2000) Stem cells: units of development, units of regeneration, and units in evolution. Cell 100: 157–68.

    Article  PubMed  CAS  Google Scholar 

  • Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, Flemming P, Franco S, Blasco MA, Manns MP, et al. (2002) Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. Faseb J 16: 935–42.

    Article  PubMed  CAS  Google Scholar 

  • Wright WE, Shay JW (2002) Historical claims and current interpretations of replicative ageing. Nat Biotechnol 20: 682–88.

    Article  PubMed  CAS  Google Scholar 

  • Xing Z, Ryan MA, Daria D, Nattamai KJ, Van Zant G, Wang L, Zheng Y, Geiger H (2006) Increased hematopoietic stem cell mobilization in aged mice. Blood 108: 2190–97.

    Article  PubMed  CAS  Google Scholar 

  • Yakoub-Agha I, Mesnil F, Kuentz M, Boiron JM, Ifrah N, Milpied N, Chehata S, Esperou H, Vernant JP, Michallet M, et al. (2006) Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French Society of Bone Marrow Transplantation and Cell Therapy. J Clin Oncol 24: 5695–5702.

    Article  PubMed  Google Scholar 

  • Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS (2005) Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 352: 1413–24.

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki S, Iwama A, Takayanagi S, Morita Y, Eto K, Ema H, Nakauchi H (2006) Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. Embo J 25: 3515–23.

    Article  PubMed  CAS  Google Scholar 

  • Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, et al. (2003) Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88: 2300–08.

    Article  PubMed  CAS  Google Scholar 

  • Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316: 1336–41.

    Article  PubMed  CAS  Google Scholar 

  • Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, et al. (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7: 1028–34.

    Article  PubMed  CAS  Google Scholar 

  • Zhu J, Woods D, McMahon M, Bishop JM (1998) Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 12: 2997–3007.

    Article  PubMed  CAS  Google Scholar 

  • Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12: 2424–33.

    Article  PubMed  CAS  Google Scholar 

  • Zindy F, Quelle DE, Roussel MF, Sherr CJ (1997) Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and ageing. Oncogene 15: 203–11.

    Article  PubMed  CAS  Google Scholar 

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Sharpless, N.E. (2008). p16INK4a and Stem Cell Ageing: A Telomere-Independent Process?. In: Rudolph, K.L. (eds) Telomeres and Telomerase in Ageing, Disease, and Cancer. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-73709-4_9

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