title: UVB-induced COX-2 expression requires histone H3 phosphorylation at Ser10 and Ser28.
abstract: Cyclooxygenase-2 (COX-2) is an inducible enzyme that contributes to the generation of chronic inflammation in response to chemical carcinogens and environmental stresses, including ultraviolet B (UVB) irradiation. Although post-translational histone modifications are believed to have an important role in modulating transcriptional regulation of UVB-induced COX-2, the underlying biochemical mechanisms are completely unknown. Here, we show that UVB activates the p38 MAPK/MSK1 kinase cascade to phosphorylate histone H3 at Ser10 and Ser28, contributing to UVB-induced COX-2 expression. UVB has no effect on the global tri-methylation level of histone H3 (H3K4me3, H3K9me3, and H3K27me3). We observed that selected mammalian 14-3-3 proteins bind to UVB-induced phosphorylated histone H3 (Ser10 and Ser28). In particular, 14-3-3ɛ is critical for recruiting MSK1 and Cdk9 to the chromatin and subsequently phosphorylating the C-terminal domain of RNA polymerase II in the cox-2 promoter. We propose that histone H3 phosphorylation at Ser10 and Ser28 serve as critical switches to promote cox-2 gene expression by facilitating the recruitment of MSK1 and Cdk9 to the cox-2 promoter, thereby promoting RNA polymerase II phosphorylation.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Keum
authors.forename: H-G
authors.initials: HG
authors.lastname: Kim
authors.forename: A M
authors.initials: AM
authors.lastname: Bode
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Surh
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000528:radiation effects; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D006657:Histones; D018808:Transcription Factor AP-1; D012694:Serine; D051546:Cyclooxygenase 2; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D042863:Cyclin-Dependent Kinase 9; D048051:p38 Mitogen-Activated Protein Kinases; D012319:RNA Polymerase II