Inhibiting TRAF2-mediated activation of NF-kappaB facilitates induction of AP-1.
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.
Manna
Sunil K
SK
Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500 001, India. manna@cdfd.org.in
Babajan
Banaganapalli
B
Raghavendra
Pongali B
PB
Raviprakash
Nune
N
Sureshkumar
Chitta
C
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
C495275:5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D008024:Ligands; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D013830:Thiadiazoles; D018808:Transcription Factor AP-1; D048670:MAP Kinase Kinase 4