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Telomerase Inhibition in RenCa, a Murine Tumor Cell Line with Short Telomeres, by Overexpression of a Dominant Negative mTERT Mutant, Reveals Fundamental Differences in Telomerase Regulation between Human and Murine Cells¹

Freie Universität, Department of Urology, D-12200 Berlin, Germany [J. S., R. H., M. M.], and Department of Immunology and Oncology, National Centre of Biotechnology, E-28049 Madrid, Spain [E. G-S., E. S., M. A. B.]

In contrast to human primary fibroblasts, mouse embryonic fibroblasts have telomerase activity, immortalize spontaneously in culture, and can be neoplastically transformed by oncogenic insult. Ectopic expression of the human telomerase catalytic subunit, human telomerase reverse transcriptase (hTERT), in human primary cells allows both spontaneous immortalization and neoplastic transformation by oncogenes. This suggests that telomerase activity, as well as the fact that mouse telomeres are longer than human telomeres, may explain some of the differences in cellular control between human and murine cells. Telomerase inhibition in immortal or transformed human cells using dominant negative hTERT mutants leads to telomere shortening and cell death. Here we study the effect of expression of a dominant negative mutant of the catalytic subunit of mouse telomerase, mTERT-DN, in a murine kidney tumor cell line, RenCa, whose telomeres are similar in length to human telomeres. After showing initial telomerase activity inhibition and telomere shortening, all clones expressing mTERT-DN reactivated telomerase and showed normal viability, in contrast with that described for human cells. This efficient telomerase reactivation coincided with a significant increase in the endogenous TERT mRNA levels in the presence of mTERT-DN expression. The results presented here reveal the existence of fundamental differences in telomerase regulation between mice and man.

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