Crisis intervention: The role of telomerase

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Abstract
Among the most mysterious problems from both a molecular biology and medical point of view are the steps leading to the transformation of differentiated quiescent cells into oncogenic cells, which are capable of continual replication and growth. Two studies, one by Counter et al. (1) published in a recent issue of the Proceedings and a second published in this issue of the Proceedings (2), provide further evidence for a direct role(s) of telomerase in oncogenic transformation. To investigate this process, the authors took advantage of a commonly used in vitro model system for defining steps in aging and in cellular immortalization in vitro (3). As first described by Hayflick (3), normal cultured cells proliferate until they reach a discrete point in which population growth ceases. This period is termed the M1 stage of aging, or replicative senescence (Fig. 1 red; ref. 3). This block, however, can be overcome by viral oncogenes. When cells are transformed with viruses that block p53 and pRB function (e.g., SV40), they continue to proliferate for an extended period of time (Fig. 1, blue). Ultimately, the cells reach a “crisis” point (M2) with a concomitant increase in both rates of death and chromosomal abnormalities (Fig. 1, blue; refs. 4–6). Only 1 × 10−7 cells survive this stringent selection. Both M1 and M2 are therefore potential suppression pathways for tumorigenesis. In the context of this commentary, M1 and senescence and M2 and crisis are used interchangeably. It is the nature of the events in M2 (specifically the role of telomerase and telomeres) that is approached in these two reports. The effect of ectopic expression of hTERT on growth and telomere size in cells cultured in vitro. As shown in red, when primary cultures are grown in vitro, telomere size decreases. …