Novel mechanism of JNK pathway activation by adenoviral E1A
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Vasily S. Romanov1,*, Anna I. Brichkina1,2,4,*, Helen Morrison1, Tatiana V. Pospelova2,3, Valery A. Pospelov2,3, Peter Herrlich1
1 Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI), Jena, Germany
2 Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
3 St. Petersburg State University, St. Petersburg, Russia
4 Present address: Institute of Molecular and Cell Biology, A-STAR, Proteos, Singapore
* These authors contributed equally to this study
Vasily S. Romanov, email:
Keywords: adenoviral E1A; AP-1 subunit c-Jun; JNK signaling pathway; small GTPase Rac1; ERM family proteins
Received: March 5, 2014 Accepted: March 24, 2014 Published: March 25, 2014
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.
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