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Adenoviral Expression of p53 Represses Telomerase Activity through Down-Regulation of Human Telomerase Reverse Transcriptase Transcription

Departments of Obstetrics and Gynecology [T. K., S. K., M. T., M. I.] and Urology [Y. K.], School of Medicine, Kanazawa University, Ishikawa 920, Japan, and Departments of Obstetrics and Gynecology [K. H.] and Neurosurgery [H. H.], School of Medicine, Ehime University, Ehime 791-0204, Japan

Telomerase activation is a critical step in cellular immortality and oncogenesis. The activity of telomerase is known to be correlated with cell proliferation, but its regulation by cell cycle regulators is not well understood. In the present study, we examined the effects of p53 on telomerase activity. Wild-type p53 was introduced into SiHa cells via a recombinant adenoviral vector, Ad5CMV-p53, and change in telomerase activity was examined by quantitative telomerase assay. Telomerase activity in the Ad5CMV-p53-infected cells was significantly repressed 36 h after infection following down-regulation of human telomerase catalytic subunit [human telomerase reverse transcriptase (hTERT)] mRNA expression, whereas no change in telomerase activity was observed in the cells infected with control vector Ad5CMV-ß-gal. Interestingly, repression of telomerase activity was an early event that preceded cell growth inhibition or apoptosis induced by p53 overexpression, suggesting that p53 directly regulates telomerase activity. Transient expression assays using hTERT-promoter reporter constructs revealed that overexpression of p53 significantly repressed promoter activity of hTERT. 5'-Truncation of the promoter sequences revealed that the proximal core promoter region containing multiple binding sites for transcription factor Sp1 was responsible for p53-mediated transcriptional repression. Mutations in these binding sites for Sp1 led to failure of p53 to repress transcription. These findings suggest that p53 repressed telomerase activity through down-regulation of hTERT transcription and that interaction of p53 with Sp1 or other transcription factors may be involved in this regulation.

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