Adenovirus E1A targets p400 to induce the cellular oncoprotein Myc

doi:10.1073/pnas.0802095105

Adenovirus E1A targets p400 to induce the cellular oncoprotein Myc

*Cold Spring Harbor Laboratory, and
^††Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, NY 11724;
^†Molecular and Cellular Biology Program, State University of New York, Stony Brook, NY 11794; and
^¶Genetics Program, State University of New York, Stony Brook, NY 11794

Communicated by Bruce W. Stillman, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, March 1, 2008 (received for review December 11, 2007)

Abstract

Adenovirus E1A drives oncogenesis by targeting key regulatory pathways that are critical for cellular growth control. The interaction of E1A with p400 is essential for many E1A activities, but the downstream target of this interaction is unknown. Here, we present evidence that the oncoprotein transcription factor Myc is the target of this interaction. We show that E1A stabilizes Myc protein via p400 and promotes the coassociation of Myc and p400 at Myc target genes, leading to their transcriptional induction. We also show that E1A requires Myc for its ability to activate Myc-dependent gene expression and induce apoptosis, and that forced expression of Myc is sufficient to rescue the activity of an E1A-mutant defective in p400 binding. Together, these findings establish that Myc, via p400, is an essential downstream target of E1A.

Footnotes

^‡‡To whom correspondence should be addressed. E-mail: tansey{at}cshl.edu
Author contributions: K.A.T. and A.A.C. contributed equally to this work; K.A.T., A.A.C., A.V.S., Y.R.S., M.N., G.J.H., S.W.L., and W.P.T. designed research; K.A.T., A.A.C., A.V.S., Y.R.S., and M.N. performed research; K.A.T., A.A.C., A.V.S., Y.R.S., M.N., G.J.H., S.W.L., and W.P.T. analyzed data; and K.A.T., A.A.C., A.V.S., M.N., G.J.H., S.W.L., and W.P.T. wrote the paper.
↵ ^‡Present address: Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107.
↵ ^§Present address: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.
↵ ^‖Present address: National Institutes of Health, One Rockledge Center, 750, 6705 Rockledge Drive, Bethesda, MD 20892.
↵**Present address: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0802095105/DCSupplemental.