Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Biochemistry. 2005 Apr 5;44(13):5041-52.

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

Author information

  • 1Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.

Abstract

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

PMID:
15794642
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for American Chemical Society
    Loading ...
    Write to the Help Desk