IkappaB kinase alpha and p65/RelA contribute to optimal epidermal growth factor-induced c-fos gene expression independent of IkappaBalpha degradation.
Mitogenic activation of expression of immediate-early genes, such as c-fos, is controlled through signal-induced phosphorylation of constitutively bound transcription factors that is correlated with a nucleosomal response that involves inducible chromatin modifications, such as histone phosphorylation and acetylation. Here we have explored a potential role for the transcription factor NF-kappaB and its associated signaling components in mediating induction of c-fos gene expression downstream of epidermal growth factor (EGF)-dependent signaling. Here we show that EGF treatment of quiescent fibroblast does not induce the classical pathway of NF-kappaB activation through IkappaB kinase (IKK)-directed IkappaBalpha phosphorylation. Interestingly, efficient induction of c-fos transcription requires IKKalpha, one of the subunits of the IkappaB kinase complex. The NF-kappaB subunit, p65/RelA, is found constitutively associated with the c-fos promoter, and knock-out of this transcription factor significantly reduces c-fos gene expression. Importantly, EGF induces the recruitment of IKKalpha to the c-fos promoter to regulate promoter-specific histone H3 Ser(10) phosphorylation in a manner that is independent of p65/RelA. Collectively, our data demonstrate that IKKalpha and p65/RelA contribute significantly to EGF-induced c-fos gene expression in a manner independent of the classical, IkappaBalpha degradation, p65/RelA nuclear accumulation response pathway.
Anest
Vasiliki
V
Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599-7295, USA.
Cogswell
Patricia C
PC
Baldwin
Albert S
AS
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D015870:Gene Expression / Q000235:genetics; D016762:Genes, fos; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA
D017931:DNA Primers; D006657:Histones; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse