Adenovirus E4orf4 protein reduces phosphorylation of c-Fos and E1A proteins while simultaneously reducing the level of AP-1.
Adenovirus E1A protein and cyclic AMP cooperate to induce transcription factor AP-1 and viral gene expression in mouse S49 cells. We report that a protein encoded within the viral E4 gene region acts to counterbalance the induction of AP-1 DNA-binding activity by E1A and cyclic AMP. Studies with mutant adenoviruses demonstrated that in the absence of E4orf4 protein, AP-1 DNA-binding activity is induced to substantially higher levels than in wild-type virus-infected cells. The induction is the result of increased production of JunB and c-Fos proteins. Hyperphosphorylated forms of c-Fos and E1A proteins accumulate in the absence of functional E4orf4 protein. We propose that the E4orf4 protein acts to inhibit the activity of a cellular kinase that phosphorylates both the E1A and c-Fos proteins. Phosphorylation-dependent alterations in the activity of c-Fos, E1A, or some unidentified protein might, then, lead to decreased synthesis of AP-1 components. This E4 function likely plays an important role in natural infections, since a mutant virus unable to express the E4orf4 protein is considerably more cytotoxic than the wild-type virus.
Müller
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Department of Molecular Biology, Howard Hughes Medical Institute, Princeton University, New Jersey 08544-1014.
Kleinberger
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Shenk
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T
D017456:Adenovirus Early Proteins; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D017456:Adenovirus Early Proteins; D009856:Oncogene Proteins, Viral; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014764:Viral Proteins; D000242:Cyclic AMP