Human Papillomavirus-16 and related viruses cause cervical cancer, which kills approximately 500,000 women per year worldwide. This proposal aims to understand mechanisms that are crucial for the biology and pathology of HPV-16, specifically, the expression of the oncoproteins E6 and E7. Previous research has confirmed that an enhancer and the E6 promoter of HPV-16 determine epithelial specificity, feedback loops and responses host's physiology. Much less is known about regulation during epithelial differentiation and progression of cervical cancer. This project aims at analyzing mechanisms that are crucial for these aspects of the biology and pathology of HPV-16, and, if successful, should provide the information essential to discovery of a means to control the virus and to prevent these particular cancers. We have detected two nuclear matrix attachment regions (MARs), which are super-regulators of transcription, namely silencers in transiently transfected cells, but enhancers after integration into cellular DNA. We propose that enhancement reflects viral transcription in cancer cells and that integration is a step in tumor progression, while silencing corresponds to transcription during latent infection or in the basal layer of epithelia. To idenitfy the mechanisms underlying these transcriptional switches, the following variables need to be analyzed: 1) cis-acting elements within each MAR that cause the two opposite transcriptional effects; 2) factors causing the two opposite effects by screening cDNA expression libraries and by protein purification; 3) physical state, methylation and histone acetylation of HPV-16-MAR-report constructs; and 4) the effect of MARs on potential late promoters.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA091964-05
Application #
7086409
Study Section
Virology Study Section (VR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2002-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$298,205
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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