ERK1 and ERK2 activate CCAAAT/enhancer-binding protein-dependent gene transcription in response to interferon-gamma

Interferons (IFNs) regulate the expression of a number of cellular genes by activating the JAK-STAT pathway, We have recently discovered that CCAAAT/e nhancer-binding protein-beta (C/EBP-beta) induces gene transcription throug h a novel IFN response element called the gamma -IFN-activated transcriptio nal element (Roy, S. K., Wachira, S. J., Weihua, X., Hu, J., and Kalvakolan u, D. V, (2000) J. Biol. Chem. 275, 12626-12632, Here, we describe a new IF N-gamma -stimulated pathway that operates C/EBP-beta -regulated gene expres sion independent of JAK1, We show that ERKs are activated by IFN-gamma to s timulate C/EBP-beta -dependent expression. Sustained ERK activation directl y correlated with C/EBP-beta dependent gene expression in response to IFN-g amma. Mutant MKK1, its inhibitors, and mutant ERK suppressed IFN-gamma -sti mulated gene induction through the gamma -IFN-activated transcriptional ele ment. Ras and Raf activation was not required for this process. Furthermore , Raf-1 phosphorylation negatively correlated with its activity. Interestin gly, C/EBP-beta -induced gene expression required STAT1, but not JAK1. A C/ EBP-beta mutant lacking the ERK phosphorylation site failed to promote IFN- gamma stimulated gene expression. Thus, our data link C/EBP-beta to IFN-gam ma signaling through ERKs.