Molecular & Cellular Biology Program firstname.lastname@example.org University of Iowa 357 Medical Research Center Iowa City, IA 52242-1182 Phone: 319-335-7748 Fax: 319-335-7656
Molecular biology of papilloma viral gene expression in cell transformation and cancer
Human papillomavirus (HPV) infection is associated with a wide range of benign, preneoplastic, and malignant lesions of the anogenital skin and mucosa. The consequences of HPV infection are most striking in the uterine cervix. HPV DNA is found in most invasive cervical carcinomas. In benign genital HPV lesions (warts or papillomas), the viral genomes replicate as free, supercoiled circular plasmids. In many cervical carcinomas, however, HPV DNA is integrated in the cellular genome in a way that preserves a candidate viral oncogene region (the E6-E7 genes), but disrupts critical viral genes that normally regulate their expression. We have found that the HPV-16 E6-E7 gene transcription is driven by cellular factors that interact with a complex keratinocyte-dependent cis enhancer. Critical cell factors include transcriptional enhancer factor TEF-1 and its specific 'coactivator' or intermediary factor' TIF. This cell-dependent effect on the E6-E7 promoter is repressed by the papillomavirus-encoded E2 trans-acting transcription factors. HPV DNA integration together with the disruption of the viral E2 control genes thus may be one of the critical steps that trigger malignant cell growth in cervical cancer. We have shown that the E2 protein represses the viral oncogene promoter by displacing a critical upstream factor, Sp1. We study (i) cellular factors that cooperate with TEF1/TIF in keratinocyte-dependent transcriptional activation of the HPV-16 oncogenes, and (ii) the mechanism of their transcriptional regulation by the viral E2 gene products. Both approaches use state-of-the -art molecular genetics and biochemical methods to detect protein-DNA interactions at the promoter. Finally, we are also interested in the molecular epidemiology of HPV infection in the genital area and in the oral cavity.
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