Nicol Keith - Overview

Our research aims to understand the molecular basis for cancer immortality and exploit this information in the development of new cancer therapies. A central cause for the immortality of cancer cells is now known to reside in an enzyme called telomerase. Normal human somatic cells have only limited proliferative potential and this is believed to be due to progressive reduction in telomere length until a critical limit is reached resulting in permanent cell cycle arrest known as senescence. In contrast, germ cells and cancer cells are immortal and this is associated with high levels of telomerase which enables telomeres to be maintained indefinitely.

Our main focus over recent years has been to determine how telomerase gene expression is regulated and to identify the signal transduction pathways activating telomerase expression in cancer. Telomerase comprises two components, the telomerase RNA (encoded by the hTERC gene) and a reverse transcriptase (encoded by the hTERT gene), both of which are required for telomerase activity. To date, we have concentrated on the regulation of the hTERC gene. Through a combination of cloning the hTERC gene promoter sequences and examining telomerase gene expression in human cancer biopsies, we have shown that the hTERC gene is regulated at the transcriptional level. We are also investigating how the regulation of the hTERT gene is linked to signal transduction pathways and transcriptional regulators activated during the transition from the mortal to immortal phenotype.

Identification of the molecular basis for telomerase gene regulation in normal cells and its deregulation in cancer cells is pivotal for the prospects of developing new telomerase and senescence based therapeutics and diagnostics. Our current research is therefore attempting to devise and test telomerase-directed molecular theraeutic strategies based on transcriptional modulators, signal transduction inhibitors and telomerase-directed gene therapy.