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The author found a new chemotype as typified by tautomycin (TM) and tautomycetin (TC), and primarily pointed out the structural similarities and differences between ocadaic acid (OA), a specific PP2A inhibitor and TM, a PP1/PP2A inhibitor.TC is a unique polyketide compound, which was shown to be a highly specific inhibitor of PP1.To elucidate the biological effects of TC, we demonstrated that treatment of COS-7 cells with 5 mM TC for 5 h inhibits endogeneous PP1 by more than 90% without affecting PP2A activity.Using TC, it was demonstrated that PP1 is a positive regulator of Raf-1, resulting in the inactivation of the MEC-ERK pathway.In this meeting, I would like to introduce our recent findings that show TC specifically inhibits activation of NF-kB among the three TNFα effectors (NF-kB, JNK and caspase), TC inhibits T-loop phosphorylation of IKKa and IKKb, thereby preventing degradation of IkBa.Co-immunoprecipitation experiments revealed the catalytic subunit of PP 1 (PP 1 C) is involved in the IKK complex.Pull-down analysis using recombinant GST-TNFα shows that PP1C is recruited by TNFR1 together with IKK to form the complex with RIP and TAK1 upon stimulus.These results suggest that the PP1 positively regulates the TNFα-induced NF-kB pathway at the level of IKK activation.NF-kB and IKK are strongly implicated in a variety of tumor malignancies.Activated NF-kB regulates the expression of genes involved in various cancers such as c-myc, cyclin D1, matrix metalloproteinase, Bcl-sL, c-FLIP and VEGF.Inhibition of NF-kB alone or in combination with cancer therapies leads to tumor cell death or growth inhibition.For example, thalidomide blocks NF-kB activation via suppression of IKK activity and is shown to inhibit NF-kB in multiple myeloma.The small molecule inhibitor of IKK, PS-1145 was found to be selectively toxic for subtypes of diffuse large B-cell lymphoma cells that are associated with NF-kB activation.Thus, TC and its well-designed analogs might be another member of IKK inhibitor and a potential candidate to treatment of certain types of cancer or even prevent them.