Regulation of Hypoxia-inducible Factor 1 by Glucose Availability under Hypoxic Conditions

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Hypoxia-inducible transcription factor 1 (HIF-1), consisting of HIF-1α and HIF-1βsubunits, regulates the expression of a variety of genes involved in diverse adaptiveprocesses in response to hypoxia. While oxygen availability regulates HIF-1α byproteolytic degradation, some growth factors regulate HIF-1α by protein synthesis inpart through mammalian target of rapamycin complex 1 (TORC1) pathway. Weherein report the role of nutrient availability on the regulation of HIF-1. A reducedavailability of glucose, not amino acids, results in a decrease of the expression ofHIF1-dependent genes and HIF-1α protein in response to hypoxia. HIF-1α mRNAexpression was not significantly suppressed and DMOG, an inhibitor for proteasomaldegradation of HIF-1α, did not induce HIF-1α protein expression under hypoxiacombined with glucose depletion. In comparison to the effect in the presence ofglucose, glucose depletion under hypoxia induced a much stronger activation of theAMP-dependent kinase pathway and phosphorylation of eIF2α, and nearly completeinhibition of the TORC1 pathway. These findings imply that the reduced availability ofglucose under hypoxia downregulates HIF-1 in part through the inhibition ofHIF-1α mRNA translation, which is occasionally observed in pathophysiologicalsituations such as ischemic diseases.
神戸大学の論文