| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 281, Issue 34, 24171-24181, August 25, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Induces Hypoxia-inducible Factor-1 Stabilization through Selective Inhibition of PHD2 Expression*
122
34
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.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Patel, C. S. Gonsalves, P. Malik, and V. K. Kalra Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1{alpha} Blood, August 1, 2008; 112(3): 856 - 865. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Gerber and J. S. Pober IFN-{alpha} Induces Transcription of Hypoxia-Inducible Factor-1{alpha} to Inhibit Proliferation of Human Endothelial Cells J. Immunol., July 15, 2008; 181(2): 1052 - 1062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. Silvestre, Z. Mallat, A. Tedgui, and B. I. Levy Post-ischaemic neovascularization and inflammation Cardiovasc Res, May 1, 2008; 78(2): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A Kingsley, P. G J Fournier, J. M Chirgwin, and T. A Guise Molecular Biology of Bone Metastasis Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 443 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-N. Jung, W. K. Yang, J. Kim, H. S. Kim, E. J. Kim, H. Yun, H. Park, S. S. Kim, W. Choe, I. Kang, et al. Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells Carcinogenesis, April 1, 2008; 29(4): 713 - 721. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Page, D. A. Chan, A. J. Giaccia, M. Levine, and D. E. Richard Hypoxia-inducible Factor-1{alpha} Stabilization in Nonhypoxic Conditions: Role of Oxidation and Intracellular Ascorbate Depletion Mol. Biol. Cell, January 1, 2008; 19(1): 86 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Kingsley, P. G.J. Fournier, J. M. Chirgwin, and T. A. Guise Molecular Biology of Bone Metastasis Mol. Cancer Ther., October 1, 2007; 6(10): 2609 - 2617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. W. J. Young, O. W. Williams, D. Chandra, L. K. Bellinghausen, G. Perez, A. Suarez, M. J. Tuvim, M. G. Roy, S. N. Alexander, S. J. Moghaddam, et al. Central Role of Muc5ac Expression in Mucous Metaplasia and Its Regulation by Conserved 5' Elements Am. J. Respir. Cell Mol. Biol., September 1, 2007; 37(3): 273 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Sanders and J. R. Hoidal The NOX on Pulmonary Hypertension Circ. Res., August 3, 2007; 101(3): 224 - 226. [Full Text] [PDF]
|
|
|
|
|
|
C. Peyssonnaux, P. Cejudo-Martin, A. Doedens, A. S. Zinkernagel, R. S. Johnson, and V. Nizet Cutting Edge: Essential Role of Hypoxia Inducible Factor-1{alpha} in Development of Lipopolysaccharide-Induced Sepsis J. Immunol., June 15, 2007; 178(12): 7516 - 7519. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
