Telomeres, the extreme ends of the eukaryotic chromosomes, are tandemly repeated specialized sequences that are implicated in maintaining chromosome stability and providing protection against illegitimate recombination and enzymatic degradation. The shortening of the telomeres is believed to function as a """"""""mitotic clock"""""""" eventually signaling senescence when a critical threshold level is reached. Human cells in culture escape senescence and acquire the capability of proliferating indefinitely probably by reactivating or upregulating telomerase and thus stabilizing the chromosomal ends. In contrast to most normal human somatic cells, telomerase activity is detected in immortalized cell lines and in about 85% of human cancers. The upregulation of the telomerase activity is thought to confer upon cancer cells the proliferative capacity to accumulate necessary mutations to become malignant. It is then conceivable that inhibition of the telomerase activity may block immortalization of cells in vitro and acquisition of malignant potential and/or reversal of the malignant phenotype in vivo thus providing """"""""proof of principle"""""""" for a causal link between telomerase and cellular immortality and cancer. Telomerase activity is crucial for cellular immortality and carcinogenesis and that telomerase inhibitors, especially against its RNA moiety, may be useful chemopreventive agents. The goal of the study is a) to evaluate telomerase antagonists in validating a causal link between telomerase, cell immortalization, and cancer and b) to assess its appropriateness as a molecular target for chemoprevention.
| Ouellette, M M; Liao, M; Herbert, B S et al. (2000) Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J Biol Chem 275:10072-6 |
