Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways

Interferons (IFNs) inhibit cell growth in a Stat1-dependent fashion that in volves regulation of c-my expression. IFN-gamma suppresses c-myc in wild-ty pe mouse embryo fibroblasts, but not in Stat1-null cells, where IFNs induce c-myc mRNA rapidly and transiently, thus revealing a novel signaling pathw ay, Both tyrosine and serine phosphorylation of Stat1 are required for supp ression. Induced expression of c-myc is likely to contribute to the prolife ration of Stat1-null cells in response to IFNs, IFNs also suppress platelet -derived growth factor (PDGF)-induced c-myc expression in wild-type but not in Stat1-null cells. A gamma-activated sequence element in the promoter is necessary but not sufficient to suppress c-myc expression in wild-type cel ls. In PKR-null cells, the phosphorylation of Stat1 on Ser727 and transacti vation are both defective, and c-myc mRNA is induced, not suppressed, in re sponse to IFN-gamma. A role for Raf-l in the Stat1-independent pathway is r evealed by studies with geldanamycin, an HSP90-specific inhibitor, and by e xpression of a mutant of p50(cdc37) that is unable to recruit HSP90 to the Raf-1 complex. Both agents abrogated the IFN-gamma-dependent induction of c -myc expression in Stat1-null cells.