Telomerase as a Growth-Promoting Factor

Abstract

Beyond its role in telomere maintenance, telomerase provides additional functions in tumorogenesis, DNA repair, and cell survival. Telomerase protects cells from apoptosis and necrosis, and stimulates growth in adverse conditions. Furthermore, gross overexpression of the catalytic subunit of telomerase (hTERT) may act as a hyperproliferative signal to induce a senescence-like phenotype in normal fibroblasts, which is similar to the senescence induced by overexpression of oncogenes. As some of these functions can be dissociated from telomere lengthening, the question arises as to how the mere presence of telomerase can serve as a survival and growth-promoting factor.Telomerase was discovered over a decade ago as a reverse transcriptase that adds tandem repeats at the telomeric ends, thereby preventing telomere shortening. 1 Since then a lot has been learned about the regulation of hTERT expression, its cellular localization, and its enzymatic activity. Telomere shortening was proposed to be the counting mechanism in cellular senescence, 2 and it was shown that ectopic expression of telomerase can immortalize human cells. [3][4][5][6] Two to three years ago the picture seemed very clear: telomerase is an enzyme whose sole function is to elongate telomeres. Recent data, however, suggest additional roles for telomerase in tumorogenesis, cell survival, and DNA repair, which are not directly dependent on telomere lengthening.

Genistein Represses Telomerase Activity via Both Transcriptional and Posttranslational Mechanisms in Human Prostate Cancer Cells

“…We believe that in addition to telomere length regulation, telomerase acts as a growth-promoting factor and modulates the expression of various growth-promoting factors (basic fibroblast growth factor and epidermal growth factor receptor; 24,25). In fact, some of our preliminary results indicate that number of growth-promoting factors and cell cycle regulatory components are regulated by hTERT.…”

“…These results suggest that genistein inhibits growth of prostate cancer cells not due to an increase in cell death; rather, genistein is involved in regulating the expression of genes that are involved in cell proliferation. Because telomerase provides indefinite replicative potential of cancer cells and acts as a growthpromoting factor (24,25), we examined whether telomerase activity was repressed by the treatment of genistein in prostate cancer cells.…”

“…Transcription factors that are involved in upregulation or down-regulation of hTERT transcriptional activity have been identified by various laboratories (15)(16)(17)(18)(19)(20)(21)(22)(23). Recent evidence shows that telomerase modulates expression of growthcontrolling genes and enhances cell proliferation (24,25).…”

Hallmarks of senescence in carcinogenesis and cancer therapy

“…The process of carcinogenesis involves several events that inhibit the senescence response to these traits, such as activation of telomerase that counteracts telomere-mediated replicative senescence, as well as inactivation of tumor suppressors p53 or p16, which mediates a bypass of both STASIS and the M1 stage of replicative senescence. The senescence-promoting and senescence-suppressing factors in tumor cells exist in a dynamic equilibrium, which is perhaps best illustrated by the report that overexpression of hTERT not only inhibits but -at very high levels -also promotes senescence (Gorbunova et al, 2003). Many recent studies have demonstrated that a variety of stimuli can shift this equilibrium in favor of senescence, thereby stopping the growth of tumor cells.…”

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

“…Ribosomal biogenesis is a prerequisite for growth and proliferation, and telomerase acts as a growth-promoting factor [20][21][22] . Thus, we investigated whether the inhibition of Pol I transcription by knockdown of TERT influences cellular proliferation and analysed the increase in the number of HCT116 cells stably transfected with the hTERT-specific shRNA or with the DNhTERT construct.…”