Ser-10 phosphorylation of histone H3 and immediate early gene expression in oncogene-transformed mouse fibroblasts.
Stimulation of the Ras-mitogen-activated protein kinase (MAPK) pathway by growth factors, phorbol esters, and oncoproteins results in the phosphorylation of histone H3. Rsk-2 and MSK1 have been reported to be H3 kinases activated by the Ras-MAPK signal transduction pathway. In this study, we used inhibitors of Rsk-2 and MSK1 to decide which of these kinases was responsible for the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phosphorylation of H3 in 10T(1/2) and Ciras-3 (H-ras-transformed 10T(1/2)) mouse fibroblasts. These studies demonstrated that MSK1, but not Rsk-2, was the H3 kinase activated in these cells. Furthermore, assays with Rsk-2 showed that this kinase phosphorylates H2B but not H3 in vitro. H89, a potent MSK1 inhibitor, prevented TPA induction of H3 phosphorylation and diminished the TPA-induced expression of the c-fos and urokinase plasminogen activator genes. We propose that persistent activation of the Ras-MAPK pathway and MSK1 resulting in the elevation of phosphorylated H3 levels may contribute to the aberrant gene expression observed in the oncogene-transformed cells.
Strelkov
Ileana S
IS
Manitoba Institute of Cell Biology, Winnipeg, Manitoba, R3E 0V9 Canada.
Davie
James R
JR
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D017781:Genes, Immediate-Early; D016762:Genes, fos; D006657:Histones / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010766:Phosphorylation; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D012694:Serine / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics; D018631:ras Proteins / Q000502:physiology
D006657:Histones; D012694:Serine; D004815:Epidermal Growth Factor; D019893:Ribosomal Protein S6 Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate