Ser-10 phosphorylation of histone H3 and immediate early gene expression in oncogene-transformed mouse fibroblasts

• Published in: Cancer research (Chicago, Ill.) Vol. 62; no. 1; pp. 75 - 78
• Main Authors: STRELKOV, Ileana S, DAVIE, James R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 2002
• Subjects: 3T3 Cells; Animals; Biological and medical sciences; c-fos gene; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Epidermal Growth Factor - pharmacology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Genes, fos; Genes, Immediate-Early; Histones - drug effects; Histones - genetics; Histones - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; Molecular and cellular biology; MSK1 protein; Phosphorylation; ras Proteins - physiology; Ribosomal Protein S6 Kinases - antagonists & inhibitors; Ribosomal Protein S6 Kinases - metabolism; Ribosomal Protein S6 Kinases, 90-kDa; Rsk-2 gene; Serine - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Urokinase-Type Plasminogen Activator - biosynthesis; Urokinase-Type Plasminogen Activator - genetics; Phosphorylation; Enzyme; Transferases; Rodentia; Gene expression; Cell transformation; In vitro; Signal transduction; Vertebrata; Mammalia; Mouse; Protein kinase; Animal; Malignant transformation; Established cell line; Onc gene; Mechanism of action; Fibroblast; Histone H3; Immediate early gene
• ISSN: 0008-5472

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.