title: Novel mechanism of JNK pathway activation by adenoviral E1A.
abstract: The adenoviral oncoprotein E1A influences cellular regulation by interacting with a number of cellular proteins. In collaboration with complementary oncogenes, E1A fully transforms primary cells. As part of this action, E1A inhibits transcription of c-Jun:Fos target genes while promoting that of c-Jun:ATF2-dependent genes including jun. Both c-Jun and ATF2 are hyperphosphorylated in response to E1A. In the current study, E1A was fused with the ligand binding domain of the estrogen receptor (E1A-ER) to monitor the immediate effect of E1A activation. With this approach we now show that E1A activates c-Jun N-terminal kinase (JNK), the upstream kinases MKK4 and MKK7, as well as the small GTPase Rac1. Activation of the JNK pathway requires the N-terminal domain of E1A, and, importantly, is independent of transcription. In addition, it requires the presence of ERM proteins. Downregulation of signaling components upstream of JNK inhibits E1A-dependent JNK/c-Jun activation. Taking these findings together, we show that E1A activates the JNK/c-Jun signaling pathway upstream of Rac1 in a transcription-independent manner, demonstrating a novel mechanism of E1A action.
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, D-07745 Jena, Germany.
authors.forename: Vasily S
authors.initials: VS
authors.lastname: Romanov
authors.forename: Anna I
authors.initials: AI
authors.lastname: Brichkina
authors.forename: Helen
authors.initials: H
authors.lastname: Morrison
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Pospelova
authors.forename: Valery A
authors.initials: VA
authors.lastname: Pospelov
authors.forename: Peter
authors.initials: P
authors.lastname: Herrlich
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D034741:RNA, Small Interfering; D014162:Transfection
chemical_list: D017500:Adenovirus E1A Proteins; D047628:Estrogen Receptor alpha; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering
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