Inhibiting TRAF2-mediated activation of NF-κB facilitates induction of AP-1

Abstract

The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4- thiadiazolidine (P3-25) is known to possess anti-bacterial, anti-fungal, and anti-tubercular activities. In this report, we provide evidence that P3-25 inhibits NF-κB, known to induce inflammatory and tumorigenic responses. It activates. AP-1, another transcription factor. It inhibits TRAF2-mediated NF-κB activation but not TRAF6-mediated NF-κB DNA binding by preventing its association with TANK (TRAF for NF-κB). It facilitates binding of MEKK1 with TRAF2 and thereby activates JNK and AP-1.Weprovide evidence, for the first time, that suggests that the interaction of P3-25 with TRAF2 leads to inhibition of the NF-κB pathway and activation of AP-1 pathway. These results suggest novel approaches to design of P3-25 as an anti-cancer/inflammatory drug for therapy through regulation of the TRAF2 pathway. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.