High risk human papillomaviruses are considered to be etiologic agents of cervical neoplasia, the second most common malignancy in women worldwide. Two papillomavirus oncogenes, E6 and E7, appear essential for the immortalization of genital keratinocytes. The E6 protein binds and inactivates the p53 tumor suppressor protein by ubiquitin-mediated degradation, while the E7 protein complexes with and inhibits pRb activity. In primary human keratinocytes and mammary epithelial cells, the HPV-16 E6 protein has been shown to activate telomerase, a ribonucleoprotein with reverse transcriptase-like activity that maintains telomere length. Telomerase activity is absent in most somatic cells, but is detectable in most immortalized and cancer cells. The mechanism by which E6 activates telomerase is unknown. We hypothesize that E6 activates telomerase in primary human keratinocytes by inducing the expression of telomerase mRNA. Our preliminary studies demonstrate that the E6 protein, but not E7 protein, increases the expression of telomerase mRNA in primary human keratinocytes. Our focus now is to examine the mechanism for E6-mediated increases in cellular telomerase activity. First, we will use the more quantitative RNase protection assay to confirm the results of our preliminary RT-PCR studies. Second, we will use the TRAP assay to correlate increases in telomerase expression with telomerase activity. Third, we will dissect the promoter region of the telomerase gene to identify E6-responsive transcriptional elements. The overall goal is to understand the molecular events regulating telomerase in cervical neoplasia and, potentially, to identify targets for therapeutic intervention.
| Veldman, Tim; Liu, Xuefeng; Yuan, Hang et al. (2003) Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter. Proc Natl Acad Sci U S A 100:8211-6 |
| Veldman, T; Horikawa, I; Barrett, J C et al. (2001) Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J Virol 75:4467-72 |
