Worldwide, cervical cancer is the second leading cause of cancer in women and the """"""""high risk"""""""" human papillomaviruses play a critical role in the genesis of this malignancy. The papillomaviruses encode two oncoproteins, E6 and E7, that are required for the initiation and maintenance of the malignant state as well as the induction of cell immortalization. Several of these biological activities appear related to the ability of E6 and E7 to degrade the cellular p53 and Rb tumor suppressor proteins, respectively. However, independent of its ability to degrade p53, E6 can induce cellular telomerase activity and, presumably, thereby maintain chromosome telomere length and continued cell proliferation. The rate-limiting event in cellular telomerase activity is the level of hTERT protein, the catalytic subunit of the enzyme complex. We and others have shown that the E6 protein transactivates the hTERT promoter, leading to an increase in hTERT protein and cellular telomerase activity. Our most recent studies indicate that the E6 protein associates with Myc protein and that they both bind and cooperatively activate the hTERT promoter. Interestingly, only the """"""""high risk"""""""" E6 proteins bind the hTERT promoter, further supporting the correlation between induction of telomerase and cell immortalization. The current proposal investigates the mechanism by which E6 associates with Myc, binds the hTERT promoter, and facilitates gene transcription. In addition, we will examine whether E6 augments other Myc-regulated genes and whether Myc can mimic a subset of E6-specific cellular phenotypes. The overall goal of the grant is to gain an understanding of the role of E6 in regulating gene transcription, cell growth and cell differentiation.
