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    Control of Bovine Papillomavirus E2 Function By Acetylation and the Novel E2 Interacting Protein RINT1: A Dissertation

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    Authors
    Quinlan, Edward J.
    Faculty Advisor
    Elliot J. Androphy, M.D.
    Academic Program
    Immunology and Microbiology
    UMass Chan Affiliations
    Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2012-01-27
    Keywords
    DNA-Binding Proteins
    Viral Proteins
    Bovine papillomavirus 1
    Alphapapillomavirus
    Acetylation
    Cell Cycle Proteins
    Amino Acids, Peptides, and Proteins
    Biochemical Phenomena, Metabolism, and Nutrition
    Cells
    Environmental Public Health
    Genetic Phenomena
    Immunology and Infectious Disease
    Investigative Techniques
    Neoplasms
    Therapeutics
    Virology
    Viruses
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    Abstract
    Human papillomavirus infection is the cause of more than 99% of cervical cancer cases. The current vaccine is ineffective therapeutically; highlighting the need for continued papillomavirus research. One avenue that could be explored in this regard is the function of the papillomavirus E2 regulatory proteins. HPV E2 represses expression of the viral E6 and E7 oncoproteins. Reintroduction of E2 into cervical carcinoma cells results in growth arrest and cellular senescence. Understanding the mechanism of how E2 regulates the early promoter may be key to developing new therapeutic and prophylactic vaccines. Here, we describe regulation of E2 through acetylation and possibly through direct interaction with a novel cellular interacting protein, RINT1. Histone acetyltransferase (HAT) proteins have been demonstrated to interact with Bovine Papillomavirus (BPV) and Human Papillomavirus (HPV) E2 proteins as well as enhance E2 dependant transcription luciferase reporter plasmid containing E2 binding sites. We demonstrate that HATs p300, CBP, and pCAF are limiting for E2 dependant transcriptional activation and that each protein functions independently. We have also identified that BPV-1 E2 is a substrate for acetylation by p300. Mutants of E2 that cannot be acetylated on lysines 111 or 112, display abnormal transcriptional phenotypes. Cells deficient in p300 display similar transcriptional defects that are intensified by CBP depletion. We propose that acetylation of BPV-1 E2 is necessary for transcriptional activation. Acetylation generates a binding site through which a co-factor may interact via a bromodomain. Regulation of E2 dependent transcriptional activation through a post-transcriptional modification represents a novel method through which BPV-1 controls gene expression. We also present evidence for a direct interaction between BPV-1 E2 and the cellular factor RINT1. This interaction does not appear to be critical for transcriptional regulation; however, several other functional pathways are indicated by the cellular complexes in which RINT1 functions. Some of these, such as ER/Golgi vesicular transport and hTERT independent telomere maintenance, are pathways in which E2 has no known role. Further investigation into regulation and consequences of E2 acetylation and the biological significance of the interaction between E2 and RINT1 could prove important in understanding the complex role of E2 in papillomavirus infection.
    DOI
    10.13028/n52e-f220
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31929
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/n52e-f220
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