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J Biol Chem. 2002 Jul 5;277(27):24625-30. Epub 2002 Apr 30.

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

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Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan.


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.

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