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Nucleic Acids Research Advance Access published online on March 13, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm090
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Transactivation of a DR-1 PPRE by a human constitutive androstane receptor variant expressed from internal protein translation start sites

Matthew A. Stoner1, Scott S. Auerbach2, Stephanie M. Zamule1, Stephen C. Strom3 and Curtis J. Omiecinski1,*

1Center for Molecular Toxicology & Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA, 2Department of Pharmacology, University of Washington, Seattle, WA 98195, USA and 3Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA

*To whom correspondence should be addressed. Tel: 814-863-1625; Fax: 814-863-1696; Email: cjo10{at}psu.edu

Received December 18, 2006. Revised January 10, 2007. Accepted February 1, 2007.

Downstream in-frame start codons produce amino-terminal-truncated human constitutive androstane receptor protein isoforms ({Delta}NCARs). The {Delta}NCARs are expressed in liver and in vitro cell systems following translation from in-frame methionine AUG start codons at positions 76, 80, 125, 128, 168 and 265 within the full-length CAR mRNA. The resulting CAR proteins lack the N-terminal DNA-binding domain (DBD) of the receptor, yielding {Delta}NCAR variants with unique biological function. Although the {Delta}NCARs maintain full retinoid X receptor alpha (RXR{alpha}) heterodimerization capacity, the {Delta}NCARs are inactive on classical CAR-inducible direct repeat (DR)-4 elements, yet efficiently transactivate a DR-1 element derived from the endogenous PPAR-inducible acyl-CoA oxidase gene promoter. RXR{alpha} heterodimerization with CAR1, CAR76 and CAR80 isoforms is necessary for the DR-1 PPRE activation, a function that exhibits absolute dependence on both the respective RXR{alpha} DBD and CAR activation (AF)-2 domains, but not the AF-1 or AF-2 domain of RXR{alpha}, nor CAR's DBD. A new model of CAR DBD-independent transactivation is proposed, such that in the context of a DR-1 peroxisome proliferator-activated response element, only the RXR{alpha} portion of the CAR-RXR{alpha} heterodimer binds directly to DNA, with the AF-2 domain of tethered CAR mediating transcriptional activation of the receptor complex.


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