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Identification of Pur as a New Hypoxia Response Factor Responsible for Coordinated Induction of the ₂ Integrin Family¹

Tianqing Kong^*, Melanie Scully, C. Simon Shelley^2, and Sean P. Colgan^2,

^* Renal Division, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115; Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO 80218; and Renal Division, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02115

Central to the process of inflammation are hypoxic conditions that lead to the binding of circulating leukocytes to the endothelium. We have previously shown that such binding is mediated by monocytes being able to directly sense hypoxic conditions and respond by inducing their surface expression of the ₂ integrin family of adhesion molecules. In this study, we show that coordinated induction of the ₂ integrins during direct hypoxia-sensing occurs through transcriptional activation of each of the genes by which they are encoded. Certain of the molecular mechanisms that mediate this activation in transcription are dependent upon hypoxia-inducible factor-1 (HIF-1), whereas others are HIF-1 independent. In search of these HIF-1-independent mechanisms, we identified Pur as a new hypoxia-response factor. Binding of Pur to the HIF-1-independent ₂ integrin promoters is induced by hypoxia and mutagenesis of these Pur-binding sites almost completely abolishes the ability of the promoters to respond to hypoxic conditions. Additional studies using siRNA directed against Pur also revealed a loss in the hypoxic response of the ₂ integrin promoters. Taken together, our findings demonstrate that hypoxia induces a coordinated up-regulation in ₂ integrin expression that is dependent upon transcriptional mechanisms mediated by HIF-1 and Pur.

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.

¹ This work was supported by Grants HL60569, DK50189, and DE016191 from the National Institutes of Health, Grant-in-Aid 0355696T from the Northeast Affiliate of the American Heart Association, and by a grant from the Crohn’s and Colitis Foundation of America.

² Address correspondence and reprint requests to Dr. Sean P. Colgan, Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO 80218 or Dr. Carl Simon Shelley, Massachusetts General Hospital, Department of Medicine, 149 13th Street, 8th Floor, Charlestown, MA 02129. E-mail addresses: sean.colgan{at}uchsc.edu or shelley{at}receptor.mgh.harvard.edu

³ Abbreviations used in this paper: HIF-1, hypoxia-inducible factor-1; ChIP, chromatin immunoprecipitation.