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J. Biol. Chem., Vol. 280, Issue 43, 36047-36054, October 28, 2005

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Functions of the Per/ARNT/Sim Domains of the Hypoxia-inducible Factor^*

Jinsong Yang, Lei Zhang, Paul J. A. Erbel, Kevin H. Gardner, Kan Ding¶, Joseph A. Garcia¶, and Richard K. Bruick1

From the Departments of Biochemistry, Pharmacology, and ^¶Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The heterodimeric transcription factor hypoxia-inducible factor (HIF) plays an important role in the progression of a number of processes in which O₂ availability is compromised and, as such, has become an increasingly attractive therapeutic target. Although tremendous progress has been made in recent years in unraveling the mechanisms underlying O₂-dependent regulation of HIF through its O₂-dependent degradation domain and C-terminal transactivation domain, our understanding of the contributions of other structural elements, particularly the Per/ARNT/Sim (PAS)-A and PAS-B domains, to the activity of HIF is incomplete. Using insights derived from the recently determined solution structures of the HIF PAS-B domains as a starting point, we have explored the function(s) of the HIF-2 PAS domains via mutational analysis. In contrast to recent models, our data reveal that both PAS domains of the HIF- subunit are necessary for heterodimer formation but are not required to mediate other HIF functions in which PAS domains have been implicated. Because disruption of individual PAS domains compromise HIF function independent of the mechanism of HIF induction, these data demonstrate the potential utility of targeting these domains for therapeutic applications.

Received for publication, February 15, 2005 , and in revised form, August 29, 2005.

^* This work was supported by a Burroughs Wellcome Fund Career Award in the Biomedical Sciences (to R. K. B.), funds from the University of Texas Southwestern Medical Center President's Research Council (to R. K. B.), and National Institutes of Health Grants CA90601 (to K. H. G.) and CA95471 (to K. H. G. and R. K. B.). This work was conducted in a facility constructed with support from Research Facilities Improvement Program Grant C06 RR-15437. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

¹ Michael L. Rosenberg Scholar in Medical Research. To whom correspondence should be addressed: Dept. of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038. Tel.: 214-648-6477; Fax: 214-648-0320; E-mail: Richard.Bruick{at}UTSouthwestern.edu.

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