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J. Biol. Chem., Vol. 278, Issue 4, 2677-2685, January 24, 2003
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From the Center for Molecular Toxicology and Carcinogenesis and the
Department of Veterinary Science, Pennsylvania State University,
University Park, Pennsylvania 16802
The mouse aryl hydrocarbon receptor (mAhR) is a
ligand-activated transcription factor that exists in a tetrameric, core
complex with a dimer of the 90-kDa heat shock protein, and the
hepatitis B virus X-associated protein 2 (XAP2). Transiently expressed
mAhR-YFP (yellow fluorescent protein fused with the mAhR) localizes
throughout cells, with a majority occupying nuclei. Co-expression of
XAP2 with mAhR-YFP results in a distinct redistribution to the
cytoplasm. We have utilized several approaches to attempt to identify
the mechanism by which XAP2 modulates the sub-cellular localization of
the mAhR. The nuclear export inhibitor, leptomycin B, was used to
demonstrate that XAP2 inhibits ligand-independent nucleocytoplasmic shuttling of the receptor. Results from cytoskeletal disruption and the
addition of an alternate nuclear localization sequence (NLS) to
mAhR-YFP suggest that XAP2 does not physically tether the complex in
the cytoplasm. The use of a rabbit polyclonal antibody raised against a
portion of the bipartite NLS of the mAhR revealed that XAP2 does not
appear to block access to the NLS. However, XAP2 hinders importin
The hsp90 Co-chaperone XAP2 Alters Importin
Recognition of
the Bipartite Nuclear Localization Signal of the Ah Receptor and
Represses Transcriptional Activity*
binding to the mAhR complex, suggesting that XAP2 alters the
conformation of the bipartite NLS of mAhR. XAP2 also represses the
transactivation potential of the AhR, in contrast to previously
published reports, perhaps by stabilizing the receptor complex
and/or blocking nucleocytoplasmic shuttling of the AhR complex.
*
This work was supported by Grant ES04869 from NIEHS,
National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 814-865-0400;
Fax: 814-863-1696; E-mail: ghp2@psu.edu.
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