Telomerase activation, cellular immortalization and cancer

Abstract

The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. Without new synthesis of telomeres at chromosome ends the chromosomes shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. While the mechanisms for telomerase activation in cancers have not been fully defined, they include telomerase catalytic subunit gene (hTERT) amplification and trans-activation of the hTERT promoter by the myc oncogene product. Ectopic expression of hTERT is sufficient to restore telomerase activity in cells that lack the enzyme and can immortalize many cell types. Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications.

Senescence, Telomere Shortening and Telomere Maintenance

“…8 Telomerase is composed of a ubiquitously expressed RNA subunit, hTERC, and a catalytic protein subunit hTERT, whose expression correlates with telomerase activity in most immortal cells, suggesting that it is the regulation of hTERT expression that controls telomerase activation. 9 Consistent with these observations, experimental introduction of hTERT into pre-senescent normal human fibroblasts that lack telomerase activity, reconstitutes readily detectable telomerase enzyme activity, stabilizes telomere length, and immortalizes these cells. 10 A simple model that emerges from these observations predicts that telomere shortening tightly regulates the limited lifespan of human cells and that immortal cells surmount this replicative barrier through the illegitimate expression of hTERT.…”

Disablingc-Mycin Childhood Medulloblastoma and Atypical Teratoid/Rhabdoid Tumor Cells by the Potent G-Quadruplex Interactive Agent S2T1-6OTD

“…This is of particular interest considering that the catalytic subunit of telomerase hTERT is transcriptionally regulated by c-Myc (27,78) and that activation or repression of c-Myc can alter hTERT activity in normal or tumor cells both in vitro and in vivo (22,28,(79)(80)(81)(82). However, on the other hand, our finding that S2T1-6OTD binds more potently to the c-Myc promoter sequence did not exclude a weaker binding to telomeric DNA (with 35-fold less efficiency).…”

An oncolytic adenovirus expressing granulocyte macrophage colony-stimulating factor shows improved specificity and efficacy for treating human solid tumors

“…28 The wildtype hTERT promoter has therefore been used as the transcriptional regulatory element to generate conditionally replicating oncolytic adenoviruses with high tumor specificity in most previous studies. 29 However, the relatively weak antitumor activity obtained in some tumor cells and the nonspecific viral replication obtained in normal cells have restricted the potential utility of such agents.…”