Studies of the molecular mechanisms in the regulation of telomerase activity

Abstract

Telomerase, a specialized RNA-directed DNA polymerase that extends telomeres of eukaryotic chromosomes, is repressed in normal human somatic cells but is activated during development and upon neoplasia. Whereas activation is involved in immortalization of neoplastic cells, repression of telomerase permits consecutive shortening of telomeres in a chromosome replication-dependent fashion. This cell cycle-dependent, unidirectional catabolism of telomeres constitutes a mechanism for cells to record the extent of DNA loss and cell division number; when telomeres become critically short, the cells terminate chromosome replication and enter cellular senescence. Although neither the telomere signaling mechanisms nor the mechanisms whereby telomerase is repressed in normal cells and activated in neoplastic cells have been established, inhibition of telomerase has been shown to compromise the growth of cancer cells in culture; conversely, forced expression of the enzyme in senescent human cells extends their life span to one typical of young cells. Thus, to switch telomerase on and off has potentially important implications in anti-aging and anti-cancer therapy. There is abundant evidence that the regulation of telomerase is multifactorial in mammalian cells, involving telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Several proto-oncogenes and tumor suppressor genes have been implicated in the regulation of telomerase activity, both directly and indirectly; these include c-Myc, Bcl-2, p21(WAF1), Rb, p53, PKC, Akt/PKB, and protein phosphatase 2A. These findings are evidence for the complexity of telomerase control mechanisms and constitute a point of departure for piecing together an integrated picture of telomerase structure, function, and regulation in aging and tumor development-Liu, J.-P. Studies of the molecular mechanisms in the regulation of telomerase activity.

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

“…Phosphorylation of the tyrosine residues leads to subsequent activation of phospholipase C-γ2 and calcium/protein kinase C signalling pathways [6]. Playing a role in activation of telomerase [32], protein kinase C is implicated in regulating IκB and myc proto-oncogene expression [33]. In addition, EBV infection in NPC has been shown to alter the function of p53 and MAPK signalling pathways [8,10].…”

Increased hepatic telomerase activity in a rat model of iron overload: A role for altered thiol redox state?

“…In general, there is a close correlation between telomerase activity and expression of the telomerase catalytic subunit, TERT [27]. Most differentiated human somatic cells lack both telomerase activity and TERT expression, while germ cells, some stem cells and a majority of cancers demonstrate both telomerase activity and TERT expression.…”

Clonogenic analysis reveals reserve stem cells in postnatal mammals. II. Pluripotent epiblastic‐like stem cells

“…Telomere shortening eventually causes chromosomal instability, leading to the activation of DNA damage response pathway followed by p53-dependent cell cycle arrest, senescence, and cell death (Vaziri and Benchimol, 1996). Telomerase was found to be activated in embryonic germ cells and embryonic stem cells, repressed in normal somatic cells, and reactivated in a large majority of tumor cells (Liu, 2000;Pera et al, 2000;Lin et al, 2003). Both the parental clone (Rat-A2B2) (Young and Black, 2004;Young et al, 2004) and its transfected progeny Scl-40␤ (Fig.…”

“…After isolation and growth in vitro with inhibitory agents (i.e., leukemia inhibitory factor, ESGRO, and/or fibroblast feeder layers), these cells exhibit immunological and molecular markers for undifferentiated embryonic cells (Niwa et al, 2000;Pera et al, 2000;Pesce and Scholer, 2001;Henderson et al, 2002;Cheng et al, 2003). They exhibit telomerase activity, which is consistent with their extended capability for self-renewal (Liu, 2000;Pera et al, 2000;Lin et al, 2003). When released from inhibitory control in vitro, these cells will spontaneously differentiate into and exhibit phenotypic expression markers for cells of ectodermal, mesodermal, and endodermal origin (Thomson et al, 1995(Thomson et al, , 1998Shamblott et al, 1998;Pera et al, 2000).…”