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Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7945-50. Epub 2002 Jun 4.

MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma.

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Department of Microbiology and Immunology, Molecular and Cellular Biology Program, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.


IFN-gamma induces a number of genes to up-regulate cellular responses by using specific transcription factors and the cognate elements. We recently discovered that CCAAT/enhancer-binding protein-beta (C/EBP-beta) induces gene transcription through an IFN-response element called gamma-IFN-activated transcriptional element (GATE). Using mutant cells, chemical inhibitors, and specific dominant negative inhibitors, we show that induction of GATE-driven gene expression depends on MEK1 (mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase kinase) and ERKs (extracellular signal-regulated protein kinases) but is independent of Raf-1. Interestingly in cells lacking the MEKK1 gene or expressing the dominant negative MEKK1, ERK activation, and GATE dependent gene expression is inhibited. A dominant negative MEKK1 blocks C/EBP-beta-driven gene expression stimulated by IFN-gamma. These studies describe an IFN-gamma-stimulated pathway that involves MEKK1-MEK1-ERK1/2 kinases to regulate C/EBP-beta-dependent gene expression.

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