Regulation of Rb and E2F by signal transduction cascades: divergent effects of JNK1 and p38 kinases.

The E2F transcription factor plays a major role in cell cycle regulation, differentiation and apoptosis, but it is not clear how it is regulated by non-mitogenic signaling cascades. Here we report that two kinases involved in signal transduction have opposite effects on E2F function: the stress-induced kinase JNK1 inhibits E2F1 activity whereas the related p38 kinase reverses Rb-mediated repression of E2F1. JNK1 phosphorylates E2F1 in vitro, and co-transfection of JNK1 reduces the DNA binding activity of E2F1; treatment of cells with TNFalpha had a similar effect. Fas stimulation of Jurkat cells is known to induce p38 kinase and we find a pronounced increase in Rb phosphorylation within 30 min of Fas stimulation. Phosphorylation of Rb correlated with a dissociation of E2F and increased transcriptional activity. The inactivation of Rb by Fas was blocked by SB203580, a p38-specific inhibitor, as well as a dominant-negative p38 construct; cyclin-dependent kinase (cdk) inhibitors as well as dominant-negative cdks had no effect. These results suggest that Fas-mediated inactivation of Rb is mediated via the p38 kinase, independent of cdks. The Rb/E2F-mediated cell cycle regulatory pathway appears to be a normal target for non-mitogenic signaling cascades and could be involved in mediating the cellular effects of such signals.