Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I.
Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of two subunits (HIF-1alpha and HIF-1beta), 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 IGF-I on the regulation of HIF-1 in human retinal epithelial cells. We show that IGF-I stimulates HIF-1alpha accumulation, HIF-1alpha nuclear translocation, and HIF-1 activity by regulation of HIF-1alpha expression through a posttranscriptional mechanism. In addition, we demonstrate that IGF-I stimulates HIF-1 activity through phosphatidylinositol-3-kinase/ mammalian target of rapamycin and MAPK-dependent signaling pathways leading to VEGF (vascular endothelial growth factor) mRNA expression. Three human prolyl-hydroxylases PHD-1, -2, and -3 (PHD-containing protein) and an asparaginyl-hydroxylase factor inhibiting HIF-1, which regulate HIF-1alpha 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 CoCl(2). Taken together, our data reveal that growth factors and CoCl(2), 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.
Treins
Caroline
C
Institut National de la Santé et de la Recherche Médicale, Unité 145, Institut Fédératif de Recherche 50, Faculté de Médecine, Avenue de Valombrose, 06107 Nice Cedex 2, France.
Giorgetti-Peraldi
Sophie
S
Murdaca
Joseph
J
Monthouël-Kartmann
Marie-Noëlle
MN
Van Obberghen
Emmanuel
E
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D006899:Mixed Function Oxygenases; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011494:Protein Kinases; D012333:RNA, Messenger; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C087000:EIF4EBP1 protein, human; C497442:HIF1A protein, human; C546842:MTOR protein, human; C069329:RPS6KA1 protein, human