Role of MSK1 in the Malignant Phenotype of Ras-transformed Mouse Fibroblasts
| Autor: | Shihua He, James R. Davie, Shannon Healy, Bojan Drobic, Soma Mandal, Paula S. Espino, Beatriz Pérez-Cadahía |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Transcriptional Activation
Proto-Oncogene Proteins c-jun RNA polymerase II Oncogene Protein p21(ras) Regulatory Sequences Nucleic Acid Ribosomal Protein S6 Kinases 90-kDa Biochemistry Chromatin remodeling Cell Line Histones Mice chemistry.chemical_compound Histone H3 Transcription (biology) Phorbol Esters Gene expression Animals Phosphorylation Genes Immediate-Early Molecular Biology Sulfonamides Gene knockdown biology Cell Biology Fibroblasts Chromatin Assembly and Disassembly Isoquinolines Molecular biology Chromatin Cell Transformation Neoplastic Phenotype 14-3-3 Proteins chemistry Cyclooxygenase 2 Phosphoserine biology.protein Proto-Oncogene Proteins c-fos |
| Zdroj: | Journal of Biological Chemistry. 286:42-49 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.156687 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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