REVIEW: The Tumor Cell and Telomerase

M. L. Altshuler^*, S. E. Severin, and A. I. Glukhov

Moscow Institute of Medical Ecology, Health Care Department of Moscow, Simferopolsky Bulvar 8, Moscow 117638, Russia; fax: (7-095) 113-4818; E-mail: 7034.g23@g23.relcom.ru

^* To whom correspondence should be addressed.

Received May 20, 2003; Revision received August 1, 2003

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Imbalanced activity of the mechanism that controls cell division is a prerequisite for malignant transformation of a normal cell. The present review considers this multi-step mechanism, which is usually called the G₁-S checkpoint. Besides, tumor cells are characterized by the presence of telomerase, an enzyme responsible for restoration of chromosome ends after replication and thus providing for unlimited cell division. The main point of the present article is to find out whether the activation of telomerase is controlled by the G₁-S checkpoint or does not depend on it. The principal components of the G₁-S checkpoint, such as cyclin-dependent kinases, retinoblastoma and E2F proteins, control the activity of telomerase. In their turn, they accumulate and transmit signals from various sources inside and outside the cell. Thus, various changes in tumor cells can activate telomerase through the G₁-S checkpoint. Such are the suggested effects on telomerase of Myc, p53, Waf1, protein kinases B and C, Wnt5A, TGFbeta, WT1, and estrogens. However, Myc, p53, WT1, estrogens, protein kinases B and C, and TGFbeta can also directly influence telomerase independently of the G₁-S checkpoint mechanism. Moreover, in 30% of human tumors the gene of the key subunit of telomerase (hTERT) is amplified, possibly due to chromosomal rearrangements unassociated with the activity of the G₁-S checkpoint. Thus, telomerase seems to be activated not by a single agent but due to combined action of various factors, both with involvement of the G₁-S checkpoint mechanism and independently of it.

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KEY WORDS: telomerase, cell cycle, malignant transformation, cancer

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