Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2

Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, vascular endothelial growth factor, and other proteins involved in O sub(2) homeostasis and tumor progression. The expression and transcriptional activity of the HIF-1 alpha subunit is regulated by the cellular O sub(2) concentration. We demonstrate that insulin, insulin-like growth factor (IGF)-1, and IGF-2 induce expression of HIF-1 alpha , which is required for expression of genes encoding IGF-2, IGF-binding protein (IGFBP)-2 and IGFBP-3. These data provide a novel mechanism by which HIF-1 alpha overexpression may occur in tumor cells and contribute to an autocrine growth factor loop.