Increased serine phosphorylation and activation of STAT1 by oncogenic Ras transfection.
Interferon (IFN)-gamma induces the activation of a signal transducer and activator of transcription 1 (STAT1), and regulates the growth response of diverse cell types. Although STAT1 activation is primarily induced upon tyrosine phosphorylation by Jak1 and Jak2 (the IFN-gamma receptor-associated tyrosine kinases), the full activation of STAT1 is thought to involve serine phosphorylation by unidentified protein kinases. As a part of our on-going investigation on the deregulation of STATs in oncogene-transformed cells, we found that STAT1 activation was efficiently induced by IFN-gamma in oncogenic Ras-transformed fibroblasts, compared to the parental fibroblasts. This was shown by target DNA binding activity, nuclear translocation, and tyrosine phosphorylation of STAT1. Using a transient transfection system, we directly demonstrated that Ras-transfection up-regulated the IFN-y-induced STAT1 activation with a concomitant increase in Erk MAPK activity. Notably, the enhanced serine phosphorylation of STAT1 was observed upon Ras-transfection, which was specifically associated with the induction of MAPK, but not Akt activity in these cells. The data suggest that Ras/MAPK module components may positively regulate STAT1 activity by inducing the serine-phosphorylation of STAT1. This would contribute to the enhanced tyrosine phosphorylation, nuclear translocation, and DNA-binding of STAT1 upon exposure of the cells to IFN-gamma in the Ras-transformed cells.
Song
Ji-Hyun
JH
Department of Biological Science and Institute for Basic Sciences, SungKyunKwan University, Suwon, Korea.
So
Eui-Young
EY
Lee
Choong-Eun
CE
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D010768:Phosphoserine; D007371:Interferon-gamma; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases