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J. Biol. Chem., Vol. 282, Issue 48, 35035-35045, November 30, 2007

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Dynamics of the Hypoxia-inducible Factor-1-Vascular Endothelial Growth Factor Promoter Complex^*

From the Division of Translational Research, Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9185

Some transactivator-promoter complexes are highly dynamic due to active disruption of the complex by proteolytic or nonproteolytic mechanisms, and this appears to be an important mechanism by which their activity is governed tightly and eventually terminated. However, the generality of these mechanisms is unclear. In this report, we address the dynamics of hypoxia-inducible factor-1 (HIF-1) binding to the vascular endothelial growth factor promoter. HIF-1 is a heterodimeric transcription factor whose activity is triggered by an increase in HIF-1 levels in hypoxic cells. A "competition ChIP" assay is employed to demonstrate that HIF-1 forms a kinetically stable complex with the native vascular endothelial growth factor promoter that has a half-life in excess of 1 h. Thus, HIF-1 activity does not require rapid proteolytic turnover of the promoter-bound transactivator, nor is the activator-promoter complex constantly disassembled by chaperones. However, we do find that after cessation of the inducing signal, HIF-1 activity is slowly returned to basal levels by proteasome-mediated proteolysis of the promoter-bound HIF-1 protein.

Received for publication, September 10, 2007 , and in revised form, October 3, 2007.

^* This work was supported by National Institutes of Health Grant GM66380. 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 supplemental Figs. S1-S9.

¹ To whom correspondence should be addressed: University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9185. E-mail: Thomas.kodadek{at}utsouthwestern.edu.

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