The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation.
Phosphorylation of histone H3 protein at serine 10 is an important step in chromatin remodeling during transcriptional transactivation. IkappaB kinase-alpha (IKK-alpha) and Mitogen- and Stress-activated protein Kinases 1 and 2 (MSK1/2) have been shown to play key roles in the transcriptional regulation of immediate early genes such as c-fos. Interestingly, IKK-alpha and MSK1/2 have also been implicated as histone H3-Ser10 kinases. In this work, we have shown that MSK1/2 are required for epidermal growth factor (EGF)-induced, but not tumor necrosis factor-induced, histone H3-Ser10 phosphorylation, both globally and at specific promoters. Consistent with this, MSK1/2 are required for optimal immediate early c-fos transcription in response to EGF potentially through control of both H3-Ser10 and promoter-associated cAMP-response element-binding protein phosphorylation. Furthermore, MSK1/2 control EGF-induced IkappaB alpha promoter H3-Ser10 phosphorylation in the absence of elevated transcription. These studies demonstrate the existence of pathway-specific mechanisms to control histone H3-Ser10 phosphorylation and gene expression.
Duncan
Elizabeth A
EA
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, USA.
Anest
Vasiliki
V
Cogswell
Patricia
P
Baldwin
Albert S
AS
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006657:Histones / Q000737:chemistry*; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*; D012694:Serine / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D006657:Histones; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D012694:Serine; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1