Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB
Abstract
Retinoid X receptor alpha (RXRα) and its N-terminally truncated version, tRXRα, are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXRα and tRXRα requires the identification of their modulators that could produce therapeutic effects. Here, we report that a class of nitrostyrene derivatives bind to RXRα by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXRα are required for binding. The binding results in the potent activation of Gal4-DBD-RXRα-LBD transactivation. However, the binding inhibits the transactivation of RXRα homodimer, which might be due to the distinct conformation of RXRα homodimer induced by these nitrostyrene derivatives. Two RXRα point mutants with Cys432 substituted with Tyr and Trp, respectively, could mimic the bindings of two nitrostyrene derivatives and have the ability of autotransactivation. In studying the functional consequences of the binding, we show that these nitrostyrene derivatives could potently inhibit the TNFα/NFκB signaling pathway in a tRXRα-dependent manner. tRXRα promotes TNFα-induced NF-κB activation through its interaction with TRAF2 and enhances TNFα-induced ...Continue Reading
References
Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets
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