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.
Highlights
Viruses and other intracellular pathogens exploit cellular processes for their proliferation
E1A does not bind to DNA directly but interacts with a large number of cellular proteins that are involved in the regulation of transcription, e.g. with the transcription factors TBP and RUNX3, the coactivators p300, CBP and PCAF, the corepressor CtBP, the cell cycle inhibitors retinoblastoma protein (Rb) and p21Waf1 [8,9,10]
The 12S splice form of E1A was fused with the ligand binding domain of the estrogen receptor (ER) to monitor the immediate effect of E1A activation: the chimeric E1A-ER protein remains inactive in the nonliganded form of the ER and can be activated by estradiol (E2) treatment
Summary
Viruses and other intracellular pathogens exploit cellular processes for their proliferation. The study of such viral “tricks” has helped in numerous cases to reveal cellular mechanisms. The adenoviral oncogene, E1A, a gene expressed early in the viral life cycle, together with the second adenoviral early gene, E1B, fully transforms primary rodent fibroblasts [2,3,4]. E1A is not rodent-specific: combined expression of three oncogenes, adenoviral E1A, H-RasV12 and Mdm, is sufficient to convert normal human diploid fibroblasts into cancer cells [7]. Identifying mechanisms of E1A action is relevant for the processes leading to human cancer. It may reveal yet unknown cellular mechanisms of transformation
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