Adenovirus E1A inhibits cardiac myocyte-specific gene expression through its amino terminus.
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 alpha-actins and alpha-myosin heavy chain, were selectively and potently inhibited (>90%) by E1A, while the ubiquitously expressed beta-actin promoter was only partially ( approximately 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 beta-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.
Bishopric
N H
NH
Molecular Cardiology Laboratory, SRI International, Menlo Park, California 94125, USA.
Zeng
G Q
GQ
Sato
B
B
Webster
K A
KA
D000199:Actins / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D010446:Peptide Fragments / Q000502:physiology; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley
D000199:Actins; D017500:Adenovirus E1A Proteins; D010446:Peptide Fragments; D018995:Myosin Heavy Chains