Studies of the molecular mechanisms in the regulation of telomerase activity

Telomerase, a specialized RNA-directed DNA polymerase that extends telomere s 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 p ermits consecutive shortening of telomeres in a chromosome replication-depe ndent fashion. This cell. cycle-dependent, unidirectional catabolism of tel omeres constitutes a mechanism for cells to record the extent of DNA loss a nd cell division number; when telomeres become critically short, the cells terminate chromosome replication and enter cellular senescence. Although ne ither the telomere signaling mechanisms nor the mechanisms whereby telomera se is repressed in normal cells and activated in neoplastic cells have been established, inhibition of telomerase has been shown to compromise the gro wth of cancer cells in culture; conversely, forced expression of the enzyme in senescent human cells extends their life span to one typical of young c ells. Thus, to switch telomerase on and off has potentially important impli cations in anti-aging and anticancer therapy. There is abundant evidence th at the regulation of telomerase is multifactorial in mammalian cells, invol ving telomerase gene expression, post-translational protein-protein interac tions, and protein phosphorylation. Several proto-oncogenes and tumor suppr essor genes have been implicated in the regulation of telomerase activity, both directly and indirectly; these include c-Myc, Bcl-2, p21(WAF1), Rb, p5 3, PKC, Akt/PKB, and protein phosphatase 2A. These findings are evidence fo r the complexity of telomerase control mechanisms and constitute a point of departure for piecing together an integrated picture of telomerase structu re, function, and regulation in aging and tumor development.