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Telomery i telomeraza - starzenie komórkowe - nagroda Nobla z fizjologii lub medycyny 2009

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Telomeres, telomerases and cellular senescence. 2009 Nobel Prize in physiology or medicine.
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The 2009 Nobel Prize in Physiology or Medicine was awarded to Elizabeth H Blackburn, Jack W Szostak and Carol W Greider for their discovery of how chromosomes are protected by telomeres and the enzyme telomerase. They solved a fundamental problem in biology, namely how can the ends of chromosomes (telomeres) avoid erosion during cellular divisions. First, working on unicellular organisms, such as yeast and ciliate, they demonstrated that chromosomal ends have an evolutionary conserved structure and function. Then, in a series of meticulous biochemical studies, they revealed the existence of a previously predicted enzyme, named telomerase, responsible for the synthesis of telomeres. Telomerase appeared to be a nucleoprotein, reverse transcriptase with an intrinsic RNA template. The active telomerase was shown by others in cancer but not in normal somatic cells and telomere erosion was immediately considered as a "replicometer" or mitotic clock" counting divisions of somatic normal cells and inducing permanent cell growth arrest (replicative senescence). The discovery of telomerase has deeply influenced biomedical research and paved the way for the development of cancer therapies based on telomerase inhibition. However, subsequently it appeared that cellular senescence is beneficial because it protects the division of cells with short labile chromosomes being potentially prone to cancer transformation. Recently, it has been shown that senescence is a cell stress response to telomeric and nontelomeric DNA damage induced by oncogenic viruses, oxygen or genotoxic stress and critically short or nonfunctional telomeres, respectively. This reinforced the idea of cellular senescence as a cancer barrier but raised doubts in "replicometer" as a main cause of cellular senescence. However the story seems to be even more complicated and double-dealing as senescent cells secrete a myriad of factors, including pro-inflammatory cytokines, creating a microenvironment supporting organismal ageing and the development of age-related diseases, including cancer. Altogether, it seems, that the hopes put in telomerase as a key to eternal youth turned out to be vain.
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  • Artandi S. E., DePinho R. A., 2010. Telomeres and telomerase in cancer. Carcinogenesis 31, 9-18.
  • Bandyopadhyay D., Timchenko N., Suwa T., Hornsby P. J., Campisi J., Medrano E. E., 2001. The human melanocyte: a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells. Exp. Gerontol. 36, 1265-1275.
  • Blackburn E. H., Greider C. W., Szostak J. W., 2006. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat. Med. 12, 1133-1138.
  • Blasco M. A., 2005. Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging. Embo J. 24, 1095-1103.
  • Blasco M. A., Lee H. W., Hande M. P., Samper E., Lansdorp P. M., DePinho R. A., Greider C. W., 1997. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25-34.
  • Bodnar A. G., Ouellette M., Frolkis M., Holt S. E., Chiu C. P., Morin G. B., Harley C. B., Shay J. W., Lichtsteiner S., Wright W. E., 1998. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349-352.
  • Braig M., Lee S., Loddenkemper C., Rudolph C., Peters A. H., Schlegelberger B., Stein H., Dorken B., Jenuwein T., Schmitt C. A., 2005. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660-665.
  • Brzezinska A., Magalska A., Sikora E., 2003. Proliferation of CD8+ in culture of human T cells derived from peripheral blood of adult donors and cord blood of newborns. Mech. Ageing Dev. 124, 379-387.
  • Brzezinska A., Magalska A., Szybinska A., Sikora E., 2004. Proliferation and apoptosis of human CD8(+)CD28(+) and CD8(+)CD28(-) lymphocytes during aging. Exp. Gerontol. 39, 539-544.
  • Butler R. N., Miller R. A., Perry D., Carnes B. A., Williams T. F., Cassel C., Brody J., Bernard M. A., Partridge L., Kirkwood T., Martin G. M., Olshansky S. J., 2008. New model of health promotion and disease prevention for the 21st century. Bmj 337, a399.
  • Campisi J., 2001. Cellular senescence as a tumor-suppressor mechanism. Trends Cell. Biol. 11, S27-31.
  • Campisi J., D'Adda Di Fagagna F., 2007. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell. Biol. 8, 729-740.
  • Chen Z., Trotman L. C., Shaffer D., Lin H. K., Dotan Z. A., Niki M., Koutcher J. A., Scher H. I., Ludwig T., Gerald W., Cordon-Cardo C., Pandolfi P. P., 2005. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725-730.
  • Collado M., Gil J., Efeyan A., Guerra C., Schuhmacher A. J., Barradas M., Benguria A., Zaballos A., Flores J. M., Barbacid M., Beach D., Serrano M., 2005 Tumour biology: senescence in premalignant tumours. Nature 436, 642.
  • Collado M., Blasco M. A., Serrano M., 2007. Cellular senescence in cancer and aging. Cell 130, 223-233.
  • D'Adda Di Fagagna F., 2008. Living on a break: cellular senescence as a DNA-damage response. Nat. Rev. Cancer 8, 512-522.
  • Deng Y., Chan S. S., Chang S., 2008. Telomere dysfunction and tumour suppression: the senescence connection. Nat. Rev. Cancer 8, 450-458.
  • Effros R. B., Dagarag M., Valenzuela H. F., 2003. In vitro senescence of immune cells. Exp Gerontol 38, 1243-1249.
  • Erusalimsky J. D., Skene C., 2009. Mechanisms of endothelial senescence. Exp. Physiol. 94, 299-304.
  • Finkel T., Serrano M., Blasco M. A., 2007. The common biology of cancer and ageing. Nature 448, 767-774.
  • Garbe J. C., Holst C. R., Bassett E., Tlsty T., Stampfer M. R., 2007. Inactivation of p53 function in cultured human mammary epithelial cells turns the telomere-length dependent senescence barrier from agonescence into crisis. Cell Cycle 6, 1927-1936.
  • Garinis G. A., Van Der Horst G. T., Vijg J., Hoeijmakers J. H., 2008. DNA damage and ageing: new-age ideas for an age-old problem. Nat. Cell. Biol. 10, 1241-1247.
  • Gorenne I., Kavurma M., Scott S., Bennett M., 2006. Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc. Res. 72, 9-17.
  • Greider C. W., Blackburn E. H., 1989. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337, 331-337.
  • Griffith J. D., Comeau L., Rosenfield S., Stansel R. M., Bianchi A., Moss H., De Lange T., 1999. Mammalian telomeres end in a large duplex loop. Cell 97, 503-514.
  • Harley C. B., Futcher A. B., Greider C. W., 1990. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458-460.
  • Hayflick L., Moorhead P. S., 1961. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585-621.
  • Herbig U., Ferreira M., Condel L., Carey D., Sedivy J. M., 2006. Cellular senescence in aging primates. Science 311, 1257.
  • Holliday R., 2006. Aging is no longer an unsolved problem in biology. Ann. NY Acad. Sci. 1067, 1-9.
  • Jeyapalan J. C., Sedivy J. M., 2008. Cellular senescence and organismal aging. Mech. Ageing Dev. 129, 467-474.
  • Kim N. W., Piatyszek M. A., Prowse K. R., Harley C. B., West M. D., Ho P. L., Coviello G. M., Wright W. E., Weinrich S. L., Shay J. W., 1994. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011-2015.
  • Kirkwood T. B., 2008a. A systematic look at an old problem. Nature 451, 644-647.
  • Kirkwood T. B., 2008b. Understanding ageing from an evolutionary perspective. J. Intern. Med. 263, 117-127.
  • Kuilman T., Peeper D. S., 2009. Senescence-messaging secretome: SMS-ing cellular stress. Nat. Rev. Cancer 9, 81-94.
  • Mahmoudi M., Gorenne I., Mercer J., Figg N., Littlewood T., Bennett M., 2008. Statins use a novel Nijmegen breakage syndrome-1-dependent pathway to accelerate DNA repair in vascular smooth muscle cells. Circ. Res. 103, 717-725.
  • Michaloglou C., Vredeveld L. C., Soengas M. S., Denoyelle C., Kuilman T., Van Der Horst C. M., Majoor D. M., Shay J. W., Mooi W. J., Peeper D. S., 2005. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720-724.
  • Michaloglou C., Vredeveld L. C., Mooi W. J., Peeper D. S., 2008. BRAF(E600) in benign and malignant human tumours. Oncogene 27, 877-895.
  • Muntoni A., Reddel R. R., 2005. The first molecular details of ALT in human tumor cells. Hum. Mol. Genet. 14, Spec No. 2, R191-196.
  • Nakamura A. J., Chiang Y. J., Hathcock K. S., Horikawa I., Sedelnikova O. A., Hodes R. J., Bonner W. M., 2008. Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence. Epigenetics Chromatin 1, 6.
  • Olovnikov A. M., 1973. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J. Theor. Biol. 41, 181-190.
  • Parrinello S., Samper E., Krtolica A., Goldstein J., Melov S., Campisi J., 2003. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat. Cell. Biol. 5, 741-747.
  • Prieur A., Peeper D. S., 2008. Cellular senescence in vivo: a barrier to tumorigenesis. Curr. Opin. Cell Biol. 20, 150-155.
  • Romanov S. R., Kozakiewicz B. K., Holst C. R., Stampfer M. R., Haupt L. M., Tlsty T. D., 2001. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409, 633-637.
  • Rubin H., 1997. Cell aging in vivo and in vitro. Mech. Ageing Dev. 98, 1-35.
  • Sedelnikova O. A., Horikawa I., Zimonjic D. B., Popescu N. C., Bonner W. M., Barrett J. C., 2004. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat. Cell. Biol. 6, 168-170.
  • Sedelnikova O. A., Horikawa I., Redon C., Nakamura A., Zimonjic D. B., Popescu N. C., Bonner W. M., 2008. Delayed kinetics of DNA double-strand break processing in normal and pathological aging. Aging Cell 7, 89-100.
  • Serrano M., Blasco M. A., 2001. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748-753.
  • Serrano M., Lin A. W., Mccurrach M. E., Beach D., Lowe S. W., 1997. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602.
  • Shampay J., Szostak J. W., Blackburn E. H., 1984. DNA sequences of telomeres maintained in yeast. Nature 310, 154-157.
  • Shay J. W., Roninson I. B., 2004. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 23, 2919-2933.
  • Shay J. W., Pereira-Smith O. M., Wright W. E., 1991. A role for both RB and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196, 33-39.
  • Shibata K. R., Aoyama T., Shima Y., Fukiage K., Otsuka S., Furu M., Kohno Y., Ito K., Fujibayashi S., Neo M., Nakayama T., Nakamura T., Toguchida J., 2007. Expression of the p16INK4A gene is associated closely with senescence of human mesenchymal stem cells and is potentially silenced by DNA methylation during in vitro expansion. Stem Cells 25, 2371-2382.
  • Szostak J. W., Blackburn E. H., 1982. Cloning yeast telomeres on linear plasmid vectors. Cell 29, 245-255.
  • Toussaint O., Medrano E. E., Von Zglinicki T., 2000. Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. Exp. Gerontol. 35, 927-945.
  • Von Zglinicki T., 2003. Replicative senescence and the art of counting. Exp. Gerontol. 38, 1259-1264.
  • Von Zglinicki T., Petrie J., Kirkwood T. B., 2003. Telomere-driven replicative senescence is a stress response. Nat. Biotechnol. 21, 229-230.
  • Wang C., Jurk D., Maddick M., Nelson G., Martin-Ruiz C., Von Zglinicki T., 2009. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8, 311-323.
  • Watson J. D., 1972. Origin of concatemeric T7 DNA. Nat. New Biol. 239, 197-201.
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