title: Telomere dynamics and telomerase activation in tumor progression: prospects for prognosis and therapy.
abstract: Eukaryotic telomeres provide a reservoir of redundancy to compensate for incomplete replication of chromosome ends. In multicellular eukaryotes, they are eroded by a varying number of base pairs at every cell division. When telomere repeats are critically shortened, DNA damage response pathways involving p53 (and in some cell types retinoblastoma protein) are invoked, leading to "M1 senescence" in normal cells; cancer cells, which frequently lack normal p53 and RB functions, often develop chromosomal instability leading to telomeric associations, ring chromosomes, and breakage-fusion-bridge cycles. These consequences of telomere erosion exert selection pressure for activation of the ribonucleoprotein enzyme telomerase, which adds new telomeric repeats at chromosome ends, and in vertebrates normally is active only in the germ line and the early embryo. Somatic cells that reactivate telomerase in vitro or in vivo become immortal. Telomerase activity has been found in many advanced and metastatic human cancers, suggesting that telomerase-dependent M2 immortalization may contribute to metastatic potential. When mammalian telomerases are isolated and their genes cloned and sequenced, the localization of telomerase expression in tumors may provide prognostic indicators of metastatic potential. The abrogation of telomerase function by pharmacological inhibition, genetic disruption, or repression of gene expression is a potential avenue of antimetastatic therapy.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Healy
mesh_terms: D001483:Base Sequence; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology* / Q000628:therapy; D011379:Prognosis; D012091:Repetitive Sequences, Nucleic Acid; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000502:physiology*
chemical_list: D019098:Telomerase