Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins.

摘要: Hypoxia is a common tumorigenesis enhancer, mostly owing to its impact on gene expression of many angiogenic and invasion-related mediators, some which are natural substrates for the proprotein convertase furin. Analysis furin promoters revealed presence putative binding sites hypoxia-inducible factor-1 (HIF-1), transcription complex that plays pivotal role in cellular adaptation hypoxia. In fact, we demonstrate herein levels fur mRNA, encoding furin, remarkably increased upon hypoxic challenge. Cotransfection HIF-1α dominant negative form wild-type (WT) cells or transfection promoter-reporter HIF-1-deficient indicated requirement HIF-1 promoter activation by Direct action was identified as canonical hypoxia-responsive element site with enhancer capability. The hypoxic/HIF-1 regulation correlated an proteolytic membrane-type 1 matrix metalloproteinase transforming growth factor-β1. Our findings unveil new facet physiological consequences hypoxia/HIF-1, through enhanced furin-induced processing/activation proproteins known be involved tumorigenesis.