NFkappaB-independent signaling to the cyclin D1 gene by Rac.

In this report we characterize the mechanism of Rac-mediated cyclin D1 gene expression in mouse embryonic fibroblasts. Activated Rac strongly stimulated cyclin D1 gene transcription but did not alter the half-life of cyclin D1 mRNA. Inhibition of NFkappaB signaling with the IkappaB super-repressor blocked the Rac-dependent expression of cyclin D1 mRNA, and this effect was selective since ERK-dependent cyclin D1 mRNA induction was minimally affected by super-repressor expression. However, we found that p65 activity in this system was induced by serum and not by activated Rac. Moreover, mouse cyclin D1 promoter-luciferase assays showed that Rac stimulated cyclin D1 gene expression without activating NFkappaB and that an essential Rac-regulated promoter element is located far upstream or downstream of the cyclin D1 transcription start site. We conclude that, in MEFs, Rac-mediated induction of cyclin D1 mRNA requires activation of a parallel NFkappaB pathway whereas ERK induces cyclin D1 transcription independent of NFkappaB.