A role for mixed lineage kinases in regulating transcription factor CCAAT/enhancer-binding protein-{beta}-dependent gene expression in response to interferon-{gamma}

J Biol Chem. 2005 Jul 1;280(26):24462-71. doi: 10.1074/jbc.M413661200. Epub 2005 May 4.

Abstract

Transcription factor CCAAT/enhancer-binding protein-beta (C/EBP-beta) regulates a variety of cellular functions in response to exogenous stimuli. We have reported earlier that C/EBP-beta induces gene transcription through a novel interferon (IFN)-response element called gamma-IFN-activated transcriptional element. We show here that IFN-gamma-induced, C/EBP-beta/gamma-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-beta in response to IFN-gamma by a mechanism involving decreased phosphorylation of a specific phosphoacceptor residue, Ser(64), within the transactivation domain. Decreased phosphorylation of Ser(64) was independent of IFN-gamma-stimulated ERK1/2 activation and did not require the ERK phosphorylation site Thr(189) located in regulatory domain 2 of C/EBP-beta. Together these studies provide the first evidence that MLK3 is involved in IFN-gamma signaling and identify a novel mechanism of transcriptional activation by IFN-gamma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Blotting, Western
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cell Line
  • Chromatin Immunoprecipitation
  • Enzyme Activation
  • Gene Expression Regulation
  • Gene Expression Regulation, Enzymologic*
  • Green Fluorescent Proteins / metabolism
  • Interferon-gamma / metabolism*
  • MAP Kinase Kinase Kinases / chemistry*
  • MAP Kinase Kinase Kinases / physiology*
  • Macrophages / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase Kinase Kinase 11
  • Models, Biological
  • Models, Genetic
  • Mutation
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Structure, Tertiary
  • RNA, Small Interfering / metabolism
  • Serine / chemistry
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • RNA, Small Interfering
  • Green Fluorescent Proteins
  • Serine
  • Interferon-gamma
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase Kinases