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

  1. Author:
    Roy, S. K.
    Hu, J. B.
    Meng, Q. J.
    Xia, Y.
    Shapiro, P. S.
    Reddy, S. P. M.
    Platanias, L. C.
    Lindner, D. J.
    Johnson, P. F.
    Pritchard, C.
    Pages, G.
    Pouyssegur, J.
    Kalvakolanu, D. V.

  2. Author Address

    Univ Maryland, Sch Med, Greenebaum Canc Ctr, Dept Microbiol & Immunol,Mol & Cellular Biol Prog, Baltimore, MD 21201 USA Univ Maryland, Sch Med, Greenebaum Canc Ctr, Dept Microbiol & Immunol,Mol & Cellular Biol Prog, Baltimore, MD 21201 USA Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Toxicol, Baltimore, MD 21205 USA Univ Illinois, Dept Hematol & Oncol, Chicago, IL 60612 USA Cleveland Clin Fdn, Taussig Canc Ctr, Cleveland, OH 44195 USA NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA Inst Signaling Dev Biol & Canc Res, F-06189 Nice, France Kalvakolanu DV Univ Maryland, Sch Med, Greenebaum Canc Ctr, Dept Microbiol & Immunol,Mol & Cellular Biol Prog, Baltimore, MD 21201 USA
    1. Year: 2002
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 99
    2. 12
    3. Pages: 7945-7950
  4. Type of Article: Article
  1. Abstract:

    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-P) 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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