The long term goals of the proposed research are to understand how the adenovirus E1A protein activates transcription from viral promoters, how E1A modifies transcription of cellular genes that induce cell proliferation, how adenovirus E1B-55K protein inhibits p53 function, and how human tumors can be identified that might be successfully treated by intratumoral injection of an E1B-55K deletion mutant. Control of gene expression is a fundamental aspect of nearly all biological processes;abnormal contol of gene expression contributes to many pathological processes such as the development of cancer. Understanding the molecular mechanisms of transcription control in detail should allow the design of therapeutic interventions to treat human disease such as cancer. We will use microscopic fluorescent methods to analyze the interaction of E1A conserved region 3 and other activation domains with mediator complexes, general transcription factors, and other co-activator complexes in living cells. We will use chromatin-immunoprecipitation (ChIP) to analyze the influence of E1A on PIC assembly and re-initiation by Pol II on viral chromatin in vivo. We will use ChIP on chip assays to determine how the binding of the E1A N-terminal region to CBP and p300 results in the recently discovered re-distribution of histone H3K18 acetylation, a modification that correlates with transcriptional activation. We will analyze the ability of E1B-55K to inhibit p53 function by tethering p53 in PML nuclear bodies dependent on E1B-55K sumoylation, and complete inhibition of p53 activation function by SUMO1-modification induced by a newly discovered E1B-55K SUM01-p53 ligase activity. We will also pursue the model that E1B-55K stimulates viral late gene expression by preventing an anti-viral response that inhibits viral mRNA nuclear export and translation. We will pursue current results suggesting that induction of this anti-viral response requires activation of ATM by MRN complexes activated by linear viral DNA. This work should lead to a more complete understanding of molecular interactionsthat control transcription in human cells. Understanding the mechanism by which E1B-55K stimulates viral replication in various human tumor cell lines should allow clinicians to determine which human tumors might betreated effectively by intratumoral injection of an E1B-55K deletion mutant.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Daschner, Phillip J
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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