title: Regulation of hypoxia-inducible factor 1 by glucose availability under hypoxic conditions.
abstract: Hypoxia-inducible transcription factor 1 (HIF-1), consisting of HIF-1 alpha and HIF-1 beta subunits, regulates the expression of a variety of genes involved in diverse adaptive processes in response to hypoxia. While oxygen availability regulates HIF-1 alpha by proteolytic degradation, some growth factors regulate HIF-1 alpha by protein synthesis in part through mammalian target of rapamycin complex 1 (TORC1) pathway. We herein report the role of nutrient availability on the regulation of HIF-1. A reduced availability of glucose, not amino acids, results in a decrease of the expression of HIF1-dependent genes and HIF-1 alpha protein in response to hypoxia. HIF-1 alpha mRNA expression was not significantly suppressed and DMOG, an inhibitor for proteasomal degradation of HIF-1 alpha, did not induce HIF-1 alpha protein expression under hypoxia combined with glucose depletion. In comparison to the effect in the presence of glucose, glucose depletion under hypoxia induced a much stronger activation of the AMP-dependent kinase pathway and phosphorylation of eIF2 alpha, and nearly complete inhibition of the TORC1 pathway. These findings imply that the reduced availability of glucose under hypoxia downregulates HIF-1 in part through the inhibition of HIF-1 alpha mRNA translation, which is occasionally observed in pathophysiological situations such as ischemic diseases.
authors.affiliation: Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Kenta
authors.initials: K
authors.lastname: Hara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.forename: Suirin
authors.initials: S
authors.lastname: Hamada
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yasuda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Moriyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Endo
authors.forename: Kiichi
authors.initials: K
authors.lastname: Hirota
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yonezawa
authors.forename: Masao
authors.initials: M
authors.lastname: Nagata
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokono