Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500 001, India.
J Biol Chem. 2010 Apr 9;285(15):11617-27. doi: 10.1074/jbc.M109.094961. Epub 2010 Feb 4.
The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine (P(3)-25) is known to possess anti-bacterial, anti-fungal, and anti-tubercular activities. In this report, we provide evidence that P(3)-25 inhibits NF-kappaB, known to induce inflammatory and tumorigenic responses. It activates AP-1, another transcription factor. It inhibits TRAF2-mediated NF-kappaB activation but not TRAF6-mediated NF-kappaB DNA binding by preventing its association with TANK (TRAF for NF-kappaB). It facilitates binding of MEKK1 with TRAF2 and thereby activates JNK and AP-1. We provide evidence, for the first time, that suggests that the interaction of P(3)-25 with TRAF2 leads to inhibition of the NF-kappaB pathway and activation of AP-1 pathway. These results suggest novel approaches to design of P(3)-25 as an anti-cancer/inflammatory drug for therapy through regulation of the TRAF2 pathway.
化合物 5-(4-甲氧基芳基亚氨基)-2-N-(3,4-二氯苯基)-3-氧代-1,2,4-噻二唑烷（P(3)-25）已知具有抗菌、抗真菌和抗结核活性。在本报告中，我们提供了证据表明，P(3)-25 抑制了 NF-kappaB，该因子已知会引发炎症和肿瘤发生反应。它激活了另一个转录因子 AP-1。它通过阻止其与 TANK（NF-kappaB 的 TRAF）结合来抑制 TRAF2 介导的 NF-kappaB 激活，但不抑制 TRAF6 介导的 NF-kappaB DNA 结合。它促进了 MEKK1 与 TRAF2 的结合，从而激活了 JNK 和 AP-1。我们首次提供了证据，表明 P(3)-25 与 TRAF2 的相互作用导致 NF-kappaB 途径的抑制和 AP-1 途径的激活。这些结果表明，通过调节 TRAF2 途径，设计 P(3)-25 作为抗癌/抗炎药物的新方法。
