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J. Biol. Chem., Vol. 280, Issue 8, 6561-6569, February 25, 2005

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Hypoxia-enhanced Expression of the Proprotein Convertase Furin Is Mediated by Hypoxia-inducible Factor-1

IMPACT ON THE BIOACTIVATION OF PROPROTEINS^*

Stephanie McMahon, Francine Grondin, Patrick P. McDonald¶, Darren E. Richard||, and Claire M. Dubois**

From the Immunology Division, ^¶Pulmonary Division, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4 and the ^||Centre de Recherche de l'Hôtel-Dieu de Québec, Québec, Québec G1R 2J6, Canada

Hypoxia is a common tumorigenesis enhancer, mostly owing to its impact on gene expression of many angiogenic and invasion-related mediators, some of which are natural substrates for the proprotein convertase furin. Analysis of furin promoters revealed the presence of putative binding sites for hypoxia-inducible factor-1 (HIF-1), a transcription complex that plays a pivotal role in cellular adaptation to hypoxia. In fact, we demonstrate herein that the levels of fur mRNA, encoding furin, are remarkably increased upon hypoxic challenge. Cotransfection of a HIF-1 dominant negative form in wild-type (WT) cells or transfection of a furin promoter-reporter gene in HIF-1-deficient cells indicated the requirement of HIF-1 for furin promoter activation by hypoxia. Direct HIF-1 action on the furin promoter was identified as a canonical hypoxia-responsive element site with enhancer capability. The hypoxic/HIF-1 regulation of furin correlated with an increased proteolytic activation of the substrates membrane-type 1 matrix metalloproteinase and transforming growth factor-1. Our findings unveil a new facet of the physiological consequences of hypoxia/HIF-1, through enhanced furin-induced proteolytic processing/activation of proproteins known to be involved in tumorigenesis.

Received for publication, November 23, 2004 , and in revised form, December 14, 2004.

^* This work was supported in part by the Canadian Institutes of Health Research and the Canadian Arthritis Society. 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.

Recipient of a studentship of the Fonds de la Recherche en Santé du Québec.

^** Scholar of the Fonds de la Recherche en Santé du Québec. To whom correspondence should be addressed: Immunology Division, Université de Sherbrooke, 3001, 12th North Ave., Sherbrooke, Québec J1H 5N4, Canada. Tel.: 819-564-5289; Fax: 819-564-5215; E-mail: Claire.M.Dubois{at}USherbrooke.ca.

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