Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein.

摘要: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known to mediate the toxic effects of numerous environmental contaminants, including polycyclic aromatic hydrocarbons (PAHs). Historically, binding PAHs AhR and events leading generation DNA adducts have been associated with chemical carcinogenesis. Previous investigations implicated green tea (GT) as affording protection against PAH-induced cancers in animal models. Investigations our laboratory demonstrated that GT polyphenol epigallocatechin gallate (EGCG) capable antagonizing AhR-mediated gene transcription, implicating inhibition signaling potential chemopreventive mechanism. This line investigation was directed at elucidating molecular mechanism this antagonism. Competitive assays strongly suggest EGCG does not bind ligand site, indicating compound functions through unlike typical antagonists. Affinity chromatography experiments implicate an indirect action involving direct chaperone protein, hsp90. induces conformation nuclear localization but incapable DNA. These altered correlate formation complex sedimentation characteristics different from those latent or AhR. data model which inhibits release hsp90 AhR, stabilizing intermediary state XAP2. first time has directly indication may exert its interaction common