Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How can we apply them for cancer therapy?

Abstract

Telomerase activation is observed in almost 90% of human cancers but not in normal tissues of somatic origin and thus is a critical step for multistep carcinogenesis. A more thorough understanding of telomerase regulation may provide not only a molecular basis of cancer progression but also as a way to manipulate telomerase activity as a potential therapeutic modality. Recent progress in studies on telomerase regulation has shown that telomerase activation is achieved at various steps, including transcriptional and post-transcriptional levels of the telomerase reverse transcriptase (hTERT) gene. Although a number of potentially important mechanisms of telomerase activation have been proposed, none of the current models can fully explain tumor-speci®c activation of telomerase, suggesting a need for further extensive analysis. This review includes a summary of recent works on telomerase regulation and a discussion of how we can overcome this situation.

TAK1 represses transcription of the human telomerase reverse transcriptase gene

“…Researchers have been investigating the regulatory mechanisms of telomerase that determine the immortality of cancer cells. Although the increasing evidences obtained to date have indicated that telomerase regulation is complex (Aisner et al, 2002;Katakura et al, 2005), significant research efforts have been focused on the transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene (Kyo and Inoue, 2002).…”

Quantitative relationship between functionally active telomerase and major telomerase components (hTERT and hTR) in acute leukaemia cells

“…The differential expression of telomerase in most malignant cells makes it an attractive target for cancer therapy (Mokbel, 2003;Shay and Wright, 2003); however, recent progress in studies on telomerase regulation has shown that telomerase activation is achieved by a process involving various steps including transcriptional and post-transcriptional levels of hTERT gene (Kyo and Inoue, 2002). An alternate splicing of hTERT transcript is one of the regulatory mechanisms of telomerase activity (Ulaner et al, 1998).…”

Tumor-specific expression detected with the use of an expression vector driven by human telomerase reverse transcriptase gene promoter

“…8 The vast majority of malignant tumors express telomerase whereas most normal cells do not. 9,10 Therefore, telomerase may be a good candidate for targeted therapy. Three components of the human telomerase have been identified: hTR, the telomerase-associated protein TEP1, and hTERT.…”