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.
Klein
Eric A
EA
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Yang
Chengfeng
C
Kazanietz
Marcelo G
MG
Assoian
Richard K
RK
D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases; D005347:Fibroblasts / Q000378:metabolism; D019940:Genes, bcl-1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D016328:NF-kappa B; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins