Sequential activation of hypoxia-inducible factor 1 and specificity protein 1 is required for hypoxia-induced transcriptional stimulation of Abcc8.

摘要: Cerebral ischemia causes increased transcription of sulfonylurea receptor 1 (SUR1), which forms SUR1-regulated NC(Ca-ATP) channels linked to cerebral edema. We tested the hypothesis that hypoxia is an initial signal stimulates Abcc8, gene encoding SUR1, via activation hypoxia-inducible factor (HIF1). In brain microvascular endothelial cells, SUR1 abundance and expression functional channels. Luciferase reporter activity driven by Abcc8 promoter was coexpression HIF1α. Surprisingly, a series luciferase assays studying revealed binding sites for specificity protein (Sp1), but not HIF, were required stimulation Sp1 promoters three species, chromatin immunoprecipitation analysis in rats after ischemia, indicated HIF binds HIF-binding on stimulate gene. conclude sequential two factors, Sp1, following ischemia. Sequential provides plausible molecular explanation prolonged treatment window observed inhibition end-target product, glibenclamide.