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Interferon (IFN)-γ 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-γ 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-γ 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-γ-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-γ in the Ras-transformed cells.


Interferon (IFN)-γ 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-γ 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-γ 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-γ-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-γ in the Ras-transformed cells.