Volume 272, Number 33, Issue of August 15, 1997 pp. 20584-20594
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Adenovirus E1A Inhibits Cardiac Myocyte-specific Gene Expression through Its Amino Terminus

(Received for publication, January 27, 1997, and in revised form, April 25, 1997)

From the Molecular Cardiology Laboratory, SRI International, Menlo Park, California 94125

Adenovirus E1A oncoproteins inhibit muscle-specific gene expression and myogenic differentiation by suppressing the transcriptional activating functions of basic helix-loop-helix proteins. As one approach to identifying cardiac-specific gene regulatory proteins, we analyzed the functional regions of E1A proteins that are required for muscle gene repression in cardiac cells. Myocyte-specific promoters, including the -actins and -myosin heavy chain, were selectively and potently inhibited (>90%) by E1A, while the ubiquitously expressed -actin promoter was only partially (~30%) repressed; endogenous gene expression was also affected. Distinct E1A protein binding sites mediated repression of muscle-specific and ubiquitous actin promoters. E1A-mediated inhibition of -actin required both an intact binding site for the tumor repressor proteins pRb and p107 and a second E1A domain (residues 15-35). In contrast, cardiac-specific promoter repression required the E1A amino-terminal residues 2-36. The proximal skeletal actin promoter (3 to base pair 153) was a target for repression by E1A. Although E1A binding to p300 was not required for inhibition of either promoter, co-expression of p300 partially reversed E1A-mediated transcriptional repression. We conclude that cardiac-specific and general promoter inhibition by E1A occurs by distinct mechanisms and that cardiac-specific gene expression is modulated by cellular factors interacting with the E1A p300/CBP-binding domain.

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