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 cells

In contrast to human primary fibroblasts, mouse embryonic fibroblasts have telomerase activity, immortalize spontaneously in culture, and can be neopl astic ally transformed by oncogenic insult. Ectopic expression of the human telomerase catalytic subunit, human telomerase reverse transcriptase (hTER T), in human primary cells allows both spontaneous immortalization and neop lastic 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 m urine cells. Telomerase inhibition in immortal or transformed human cells u sing 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 tel omeres, After showing initial telomerase activity inhibition and telomere s hortening, all clones expressing mTERT-DN reactivated telomerase and showed normal viability, in contrast with that described for human cells. This ef ficient telomerase reactivation coincided with a significant increase in th e endogenous TERT mRNA levels in the presence of mTERT-DN expression. The r esults presented here reveal the existence of fundamental differences in te lomerase regulation between mice and man.