Inhibition of tumor necrosis factor-alpha -induced nuclear translocation and activation of NF-kappa B by dehydroxymethylepoxyquinomicin

J Biol Chem. 2002 Jul 5;277(27):24625-30. doi: 10.1074/jbc.M112063200. Epub 2002 Apr 30.


We previously designed and synthesized an NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), that showed anti-inflammatory activity in vivo. In the present study we looked into its mechanism of inhibition. DHMEQ inhibited tumor necrosis factor-alpha (TNF-alpha)- and 12-O-tetradecanoylphorbol-13-acetate-induced transcriptional activity of NF-kappaB in human T cell leukemia Jurkat cells. It also inhibited the TNF-alpha-induced DNA binding of nuclear NF-kappaB but not the phosphorylation and degradation of IkappaB. Moreover, DHMEQ inhibited the TNF-alpha-induced nuclear accumulation of p65, a component of NF-kappaB. It also inhibited TNF-alpha-induced nuclear transport of green fluorescent protein-tagged p65. On the other hand, DHMEQ did not inhibit the nuclear transport of Smad2 and large T antigen. Also, it did not inhibit TNF-alpha-induced activation of JNK but synergistically induced apoptosis with TNF-alpha in Jurkat cells. Taken together, these data indicate that DHMEQ is a unique inhibitor of NF-kappaB acting at the level of nuclear translocation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / physiology*
  • Apoptosis / drug effects
  • Benzamides / pharmacology*
  • Cyclohexanones / pharmacology*
  • DNA-Binding Proteins / metabolism
  • Genes, Reporter
  • Green Fluorescent Proteins
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Jurkat Cells
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mitogen-Activated Protein Kinases / pharmacology
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Smad2 Protein
  • Tetradecanoylphorbol Acetate / pharmacology
  • Trans-Activators / metabolism
  • Transcription, Genetic / drug effects
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Benzamides
  • Cyclohexanones
  • DNA-Binding Proteins
  • Luminescent Proteins
  • NF-kappa B
  • SMAD2 protein, human
  • Smad2 Protein
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • dehydroxymethylepoxyquinomicin
  • Green Fluorescent Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate