Downregulation of telomerase reverse transcriptase mRNA expression by wildtype p53 in human tumor cells

The p53 tumor suppressor protein inhibits the formation of tumors through i nduction of cell cycle arrest and/or apoptosis, In the present study we dem onstrated that p53 is also a powerful inhibitor of human telomerase reverse transcriptase (hTERT), a key component for telomerase, Activation of eithe r exogenous temperature-sensitive (ts) p53 in BL41 Burkitt lymphoma cells o r endogenous wild type (wt) p53 at a physiological level in MCF-7 breast ca rcinoma cells triggered a rapid downregulation of hTERT mRNA expression, in dependently of the induction of the p53 target gene p21, Co-transfection of an hTERT promoter construct with wt p53 but not mutant p53 in HeLa cells i nhibited the hTERT promoter activity. Furthermore, the activation of the hT ERT promoter in Drosophila Schneider SL2 cells was completely dependent on the ectopic expression of Sp1 and was abrogated by wt p53, Finally, wt p53 inhibited Sp1 binding to the hTERT proximal promoter by forming a p53-Sp1 c omplex. Since activation of telomerase, widely observed in human tumor cell lines and primary tumors, is a critical step in tumorigenesis, wt p53-trig gered inhibition of hTERT/telomerase expression may reflect yet another mec hanism of p53-mediated tumor suppression. Our findings provide new insights into both the biological function of p53 and the regulation of hTERT/telom erase expression.