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J. Biol. Chem., Vol. 281, Issue 34, 24171-24181, August 25, 2006

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Transforming Growth Factor 1 Induces Hypoxia-inducible Factor-1 Stabilization through Selective Inhibition of PHD2 Expression^*

Stephanie McMahon¹, Martine Charbonneau², Sebastien Grandmont², Darren E. Richard³, and Claire M. Dubois⁴

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

The hypoxia-inducible transcription factor-1 (HIF-1) is central to a number of pathological processes through the induction of specific genes such as vascular endothelial growth factor (VEGF). Even though HIF-1 is highly regulated by cellular oxygen levels, other elements of the inflammatory and tumor microenvironment were shown to influence its activity under normal oxygen concentration. Among others, recent studies indicated that transforming growth factor (TGF) increases the expression of the regulatory HIF-1 subunit, and induces HIF-1 DNA binding activity. Here, we demonstrate that TGF acts on HIF-1 accumulation and activity by increasing HIF-1 protein stability. In particular, we demonstrate that TGF markedly and specifically decreases both mRNA and protein levels of a HIF-1-associated prolyl hydroxylase (PHD), PHD2, through the Smad signaling pathway. As a consequence, the degradation of HIF-1 was inhibited as determined by impaired degradation of a reporter protein containing the HIF-1 oxygen-dependent degradation domain encompassing the PHD-targeted prolines. Moreover, inhibition of the TGF1 converting enzyme, furin, resulted in increased PHD2 expression, and decreased basal HIF-1 and VEGF levels, suggesting that endogenous production of bioactive TGF1 efficiently regulates HIF-1-targeted genes. This was reinforced by results from HIF-1 knock-out or HIF-1-inhibited cells that show impairment in VEGF production in response to TGF. This study reveals a novel mechanism by which a growth factor controls HIF-1 stability, and thereby drives the expression of specific genes, through the regulation of PHD2 levels.

Received for publication, May 10, 2006 , and in revised form, June 29, 2006.

^* This work was supported in part by Canadian Institutes for Health Research (CIHR) Grants MOP-68944 and MOP-67021 (to C. M. D.) and MOP-49609 (to D. R.) 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 Recipient of a studentship of the Fonds de la Recherche en Santé du Québec.

² Both authors contributed equally to this work.

³ Recipient of a CIHR scholar.

⁴ To whom correspondence should be addressed: 3001, 12th North Ave., Sherbrooke, Quebec J1H 5N4, Canada. Tel.: 819-564-5289; Fax: 819-564-5215; E-mail: Claire.M.Dubois{at}USherbrooke.ca.

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