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Submitted on June 11, 2004
Accepted on January 25, 2005
INSERM U145, IFR 50, Faculté de Médecine, avenue de Valombrose, 06107 Nice Cedex 2 France
* To whom correspondence should be addressed. E-mail: peraldis{at}unice.fr.
Hypoxia Inducible Factor-1 (HIF-1), a transcription factor composed of two subunits (HIF-1
and HIF-1
), initially described as a mediator of adaptive responses to changes in tissue oxygenation, has been shown to be activated in an oxygen-independent manner. In this report, we studied the action of Insulin-like Growth Factor-1 (IGF-I) on the regulation of HIF-1 in human retinal epithelial cells. We show that IGF-I stimulates HIF-1 accumulation, HIF-1 nuclear translocation and HIF-1 activity by regulation of HIF-1 expression through a post-transcriptional mechanism. In addition, we demonstrate that IGF-I stimulates HIF-1 activity through PI-3-kinase/mTOR and MAP-kinase-dependent signaling pathways leading to VEGF (Vascular Endothelial Growth Factor) mRNA expression. Three human prolyl-hydroxylases PHD-1, -2 and -3 (Prolyl Hydroxylase Domain containing protein) and an asparaginyl-hydroxylase FIH-1 (Factor Inhibiting HIF-1), which regulate HIF-1 stability and HIF-1 activity in response to hypoxia, have been described. Our analysis of their mRNA expression showed a different magnitude and time course of expression pattern in response to insulin and IGF-I compared with CoCl2. Taken together, our data reveal that growth factors and CoCl2, which mimics hypoxia, lead to HIF-1 activation and ensuing VEGF expression by different mechanisms. Their joined actions are likely to lead to an important and sustained increase in VEGF action on retinal blood vessels, and hence to have devastating effects on the development of diabetic retinopathy.
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