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

Interferons (IFNs) regulate the expression of a number of cellular genes by activating the JAK-STAT pathway, We have recently discovered that CCAAAT/enhancer-binding protein-beta (C/EBP-beta) induces gene transcription through a novel IFN response element called the gamma -IFN-activated transcriptional element (Roy, S. K., Wachira, S. J., Weihua, X., Hu, J., and Kalvakolanu, D. V, (2000) J. Biol. Chem. 275, 12626-12632, Here, we describe a new IFN-gamma -stimulated pathway that operates C/EBP-beta -regulated gene expression independent of JAK1, We show that ERKs are activated by IFN-gamma to stimulate C/EBP-beta -dependent expression. Sustained ERK activation directly correlated with C/EBP-beta dependent gene expression in response to IFN-gamma. Mutant MKK1, its inhibitors, and mutant ERK suppressed IFN-gamma -stimulated gene induction through the gamma -IFN-activated transcriptional element. Ras and Raf activation was not required for this process. Furthermore, Raf-1 phosphorylation negatively correlated with its activity. Interestingly, 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-gamma signaling through ERKs.