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Journal of Virology, May 2009, p. 4810-4822, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02145-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Adenovirus Transforming Protein E1A Induces c-Myc in Quiescent Cells by a Novel Mechanism{triangledown}

Ravi-Kumar Kadeppagari ,{dagger},{ddagger} Natesan Sankar,{dagger} and Bayar Thimmapaya*

Microbiology and Immunology Department, Feinberg School of Medicine, Northwestern University, 303 East Chicago Ave., Chicago, Illinois 60611

Received 10 October 2008/ Accepted 26 February 2009

Previously we showed that the E1A binding proteins p300 and CBP negatively regulate c-Myc in quiescent cells and that binding of E1A to p300 results in the induction of c-Myc and thereby induction of S phase. We demonstrated that p300 and HDAC3 cooperate with the transcription factor YY1 at an upstream YY1 binding site and repress the Myc promoter. Here we show that the small E1A protein induces c-Myc by interfering with the protein-protein interaction between p300, YY1, and HDAC3. Wild-type E1A but not the E1A mutants that do not bind to p300 interfered in recruitment of YY1, p300, and HDAC3 to the YY1 binding site. As E1A started to accumulate after infection, it transiently associated with promoter-bound p300. Subsequently, YY1, p300, and HDAC3 began to dissociate from the promoter. Later in infection, E1A dissociated from the promoter as well as p300, YY1, and HDAC3. Removal of HDAC3 from the promoter correlated with increased acetylation of Myc chromatin and induction. In vivo E1A stably associated with p300 and dissociated YY1 and HDAC3 from the trimolecular complex. In vitro protein-protein interaction studies indicated that E1A initially binds to the p300-YY1-HDAC3 complex, briefly associates with it, and then dissociates the complex, recapitulating somewhat the in vivo situation. Thus, E1A binding to the C-terminal region of p300 disrupts the important corepressor function provided by p300 in repressing c-Myc. Our results reveal a novel mechanism by which a viral oncoprotein activates c-Myc in quiescent cells and raise the possibility that the oncoproteins encoded by the small-DNA tumor viruses may use this mechanism to induce c-Myc, which may be critical for cell transformation.

* Corresponding author. Mailing address: Northwestern University, Feinberg School of Medicine, Microbiology and Immunology Department, 303 East Chicago Ave., Chicago, IL 60611. Phone: (312) 503-5224. Fax: (312) 503-0389. E-mail: b-thimmapaya{at}northwestern.edu

{triangledown} Published ahead of print on 11 March 2009.

{dagger} These two authors contributed equally to this article.

{ddagger} Present address: Dept. of Microbiology, Immunology and Parasitology, LSU Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112.

Journal of Virology, May 2009, p. 4810-4822, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02145-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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