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[Cancer Research 59, 1539-1543, April 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 1539-1543, April 1, 1999]
© 1999 American Association for Cancer Research

Molecular Biology and Genetics

Expression of Catalytically Active Telomerase Does Not Prevent Premature Senescence Caused by Overexpression of Oncogenic Ha-Ras in Normal Human Fibroblasts1

Shan Wei, Wenyi Wei and John M. Sedivy2

Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02912

All normal cells in culture display a limited capacity to divide and eventually undergo an irreversible growth arrest known as replicative cellular senescence. The development of cellular immortality has been implicated as an important factor in the progression of human cancers. Expression of telomerase has been shown to elicit a bypass of senescence and the acquirement of an extended life span. Although oncogenic Ras induces malignant transformation in most immortal cells, it has been shown to cause a senescence-like cell cycle arrest in presenescent human fibroblasts. To test the relationship between the senescence-inducing effect of Ras and the senescence-bypassing activity of telomerase, we used retroviral vector infection to introduce the catalytic subunit of human telomerase into normal human lung fibroblasts. Cell clones displaying in vitro telomerase catalytic activity and life span extension were obtained. However, these cells still became senescent after infection with a retrovirus vector expressing oncogenic Ha-Ras. No differences in premature senescence phenotypes between normal and telomerase-expressing cells were observed. A small number of colonies were recovered after the introduction of Ha-Ras into either normal or telomerase-expressing cells, but in all cases, these clones failed to express the exogenously introduced Ras. We propose that even in the presence of active telomerase, the cellular senescence machinery remains intact and can be activated by appropriate signals. Consequently, interventions aimed at the activation of the latent senescence program may be a fruitful approach in cancer therapy.




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Copyright © 1999 by the American Association for Cancer Research.