Mitogen- and stress-activated protein kinase 1 activity and histone h3 phosphorylation in oncogene-transformed mouse fibroblasts.
Activation of the Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-ERK signal transduction pathway or the SAPK2/p38 pathway results in the activation of mitogen- and stress-activated protein kinase 1 (MSK1). This activation of MSK1 leads to a rapid phosphorylation of histone H3 at Ser(10). Previously, we had demonstrated that Ser(10) phosphorylated H3 was elevated in Ciras-3 (c-Ha-ras-transformed 10T12) mouse fibroblasts and that H3 phosphatase activity was similar in Ciras-3 and 10T12 cells. Here, we demonstrate that the activities of ERK and MSK1, but not p38, are elevated in Ciras-3 cells relative to these activities in the parental 10T12 cells. Analyses of the subcellular distribution of MSK1 showed that the H3 kinase was similarly distributed in Ciras-3 and 10T12 cells, with most MSK1 being present in the nucleus. In contrast to many other chromatin modifying enzymes, MSK1 was loosely bound in the nucleus and was not a component of the nuclear matrix. Our results provide evidence that oncogene-mediated activation of the Ras-mitogen-activated protein kinase signal transduction pathway elevates the activity of MSK1, resulting in the increased steady-state levels of phosphorylated H3, which may contribute to the chromatin decondensation and aberrant gene expression observed in these cells.
Drobic
Bojan
B
Manitoba Institute of Cell Biology, Department of Biochemistry, University of Manitoba, Winnipeg, Manitoba, Canada.
Espino
Paula S
PS
Davie
James R
JR
D000818:Animals; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D011905:Genes, ras / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D014162:Transfection
D006657:Histones; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1