Stat1-independent regulation of gene expression in response to IFN-gamma

Although Stat1 is essential for cells to respond fully to IFN-gamma, there is substantial evidence that, in the absence of Stat1, IFN-gamma can still regulate the expression of some genes, induce an antiviral state and affect cell growth. We have now identified many genes that are regulated by IFN-g amma in serum-starved Stat1-null mouse fibroblasts. The proteins induced by IFN-gamma in Stat1-null cells can account for the substantial biological r esponses that remain. Some genes are induced in both wild-type and Stat1-nu ll cells and thus are truly Stat1-independent. Others are subject to more c omplex regulation in response to IFN-gamma, repressed by Stat1 in wild-type cells and activated in Stat1-null cells. Many genes induced by IFN-gamma i n Stat1-null fibroblasts also are induced by platelet-derived growth factor in wild-type cells and thus are likely to be involved in cell proliferatio n. In mouse cells expressing the docking site mutant Y440F of human IFN-gam ma receptor subunit 1, the mouse Stat1 is not phosphorylated in response to human IFN-gamma. but c-myc and c-jun are still induced, showing that the S tat1 docking site is not required for Stat1-independent signaling.