Role of MSK1 in the malignant phenotype of Ras-transformed mouse fibroblasts.
Activated by the RAS-MAPK signaling pathway, MSK1 is recruited to immediate-early gene (IEG) regulatory regions, where it phosphorylates histone H3 at Ser-10 or Ser-28. Chromatin remodelers and modifiers are then recruited by 14-3-3 proteins, readers of phosphoserine marks, leading to the occupancy of IEG promoters by the initiation-engaged form of RNA polymerase II and the onset of transcription. In this study, we show that this mechanism of IEG induction, initially elucidated in parental 10T1/2 murine fibroblast cells, applies to metastatic Hras1-transformed Ciras-3 cells. As the RAS-MAPK pathway is constitutively activated in Ciras-3 cells, MSK1 activity and phosphorylated H3 steady-state levels are elevated. We found that steady-state levels of the IEG products AP-1 and COX-2 were also elevated in Ciras-3 cells. When MSK1 activity was inhibited or MSK1 expression was knocked down in Ciras-3 cells, the induction of IEG expression and the steady-state levels of COX-2, FRA-1, and JUN were greatly reduced. Furthermore, MSK1 knockdown Ciras-3 cells lost their malignant phenotype, as reflected by the absence of anchorage-independent growth.
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada.
Beatriz
B
Pérez-Cadahía
Bojan
B
Drobic
Paula S
PS
Espino
Shihua
S
He
Soma
S
Mandal
Shannon
S
Healy
James R
JR
Davie
D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D017781:Genes, Immediate-Early / Q000235:genetics; D006657:Histones / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000235:genetics*; D010641:Phenotype; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D000099169:Fos-Related Antigen 1
D048948:14-3-3 Proteins; D051546:Cyclooxygenase 2; D006657:Histones; D007546:Isoquinolines; D015689:Oncogene Protein p21(ras); D010703:Phorbol Esters; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D013449:Sulfonamides; D000099169:Fos-Related Antigen 1; C116919:mitogen and stress-activated protein kinase 1; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide