A role for mixed lineage kinases in regulating transcription factor CCAAT/enhancer-binding protein-β-dependent gene expression in response to interferon-γ

Abstract

Transcription factor CCAAT/enhancer-binding protein-β (C/EBP-β) regulates a variety of cellular functions in response to exogenous stimuli. We have reported earlier that C/EBP-β induces gene transcription through a novel interferon (IFN)-response element called γ-IFN-activated transcriptional element. We show here that IFN-γ-induced, C/EBP-β/γ-IFN-activated transcriptional element-dependent gene expression is regulated by mixed lineage kinases (MLKs), members of the mitogen-activated protein kinase kinase kinase family. MLK3 appears to activate C/EBP-β in response to IFN-γ by a mechanism involving decreased phosphorylation of a specific phosphoacceptor residue, Ser64, within the transactivation domain. Decreased phosphorylation of Ser64 was independent of IFN-γ-stimulated ERK1/2 activation and did not require the ERK phosphorylation site Thr189 located in regulatory domain 2 of C/EBP-β. Together these studies provide the first evidence that MLK3 is involved in IFN-γ signaling and identify a novel mechanism of transcriptional activation by IFN-γ.