Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kappaB-mediated gene expression in airway epithelial cells

Am J Respir Cell Mol Biol. 2003 Jun;28(6):762-9. doi: 10.1165/rcmb.2002-0261OC. Epub 2003 Jan 31.


In 16HBE14o- human bronchial epithelial cells, maximal tumor necrosis factor (TNF)-alpha-induced interleukin (IL)-8 expression depends on the activation of two distinct signaling pathways, one constituted in part by activator protein (AP)-1 and the other by nuclear factor (NF)-kappaB. We examined the upstream signaling intermediates responsible for IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in this system, hypothesizing that p21 Ras and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase (MEKK)-1 function as common upstream activators of both the AP-1 and NF-kappaB pathways. TNF-alpha treatment induced both Ras and MEKK1 activation. Dominant-negative forms of Ras (N17Ras) and MEKK1 (MEKK1-KM) each inhibited TNF-alpha-induced transcription from IL-8 and GM-CSF promoters. Ras was required for maximal activation of extracellular signal-regulated kinase (ERK) and Jun amino terminal kinase (JNK) as well as AP-1 and NF-kappaB transcriptional activities, but not for activation of IkappaB kinase (IKK)-beta, an upstream activator of NF-kappaB. MEKK1 was required for maximal activation of ERK, JNK, and IKK, as well as for maximal AP-1 and NF-kappaB transcriptional activities. We conclude that Ras regulates TNF-alpha-induced chemokine expression by activating the AP-1 pathway and enhancing transcriptional function of NF-kappaB, whereas MEKK1 activates both the AP-1 and NF-kappaB pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Bronchi / cytology
  • Cells, Cultured
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Humans
  • Interleukin-8 / genetics
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1*
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Promoter Regions, Genetic
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction / physiology
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Interleukin-8
  • NF-kappa B
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Protein Kinases
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • ras Proteins