Myc activates telomerase
Abstract
Telomere maintenance has been proposed as an essential prerequisite to human tumor development. The telomerase enzyme is itself a marker for tumor cells, but the genetic alterations that activate the enzyme during neoplastic transformation have remained a mystery. Here, we show that Myc induces telomerase in both normal human mammary epithelial cells (HMECs) and normal human diploid fibroblasts. Myc increases expression of hEST2 (hTRT/TP2), the limiting subunit of telomerase, and both Myc and hEST2 can extend the life span of HMECs. The ability of Myc to activate telomerase may contribute to its ability to promote tumor formation.
Telomerase activity is largely absent from somatic cells in vivo and from normal human cells in culture (Counter et al. 1992). As these cells proliferate, telomeric repeats are progressively lost as a result of incomplete replication of chromosome ends during each division cycle (Watson 1972; Olovnikov 1973; Harley et al. 1990; Hastie et al. 1990). Telomere shortening has been proposed as the mitotic clock that marks the progress of a cell toward the end of its replicative life span. According to this model, erosion of chromosome ends triggers cellular senescence (Harley et al. 1990; for review, see Harley 1991). Bypass of senescence can be accomplished by negation of tumor suppressor pathways (e.g., p53 and Rb/p16). This allows continued proliferation (extended life span) that is accompanied by further telomere loss (Counter et al. 1992). Indefinite proliferation in the absence of a telomere maintenance strategy would eventually result in a complete loss of telomeres and in destabilization of chromosomes (Singer and Gottschling 1994). Because this situation is probably incompatible with survival, cells with an indeterminate life span must adopt strategies for telomere conservation. As predicted, cells that emerge from extended life span as immortal cell lines often activate the telomerase enzyme (Counter et al. 1992; Kim et al. 1994).
Cells that are programmed for continuous proliferation generally maintain telomere length. For example, many stem cell populations possess telomerase activity (Counter et al. 1992; Kim et al. 1994). Telomerase is also induced in mitogen-stimulated lymphocytes and is detected in mitotically active regions of hair follicles and intestinal crypts (for review, see Greider 1998). The association of telomerase with cell proliferation has led to the hypothesis that telomere maintenance is simply a housekeeping function. However, proliferating normal cells in culture generally lack telomerase activity (Counter et al. 1992; Kim et al. 1994).
Stabilization of telomeric repeats may be a prerequisite for tumorigenesis (Counter et al. 1992). Consistent with this notion, telomerase is activated in a high percentage of late-stage human tumors and is present in most tumor-derived cell lines in culture (Counter et al. 1992, 1994; Kim et al. 1994; Shay and Wright 1996). To test the role of telomere maintenance in tumorigenesis, we surveyed known oncogenes for their ability to activate telomerase.
Acknowledgments
We thank R. Weinberg for providing the full-length hEST2 cDNA. HMECs were a kind gift of M. Stampfer. We thank B. Tansey for helpful discussions and for providing the TFIIB antibody. This work was supported by a grant from the U.S. Army Breast Cancer research program (DAMD17-96-1-6053) and in part by funds from the National Institutes of Health. D. Beach is supported by the Hugh and Catherine Stevenson Fund. G. Hannon is a Pew Scholar in the Biomedical Sciences.
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Footnotes
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