Regulation of hypoxia-inducible factor 1 by glucose availability under hypoxic conditions.
Regulation of hypoxia-inducible factor 1 by glucose availability under hypoxic conditions.
复制标题
DOI：
--
复制
发表时间：
2007-12
期刊：
影响因子：
--
通讯作者：
Jing Zhou;K. Hara;M. Inoue;S. Hamada;H. Yasuda;H. Moriyama;H. Endo;K. Hirota;K. Yonezawa;M. Nagata;K. Yokono
中科院分区：
文献类型：
--
作者：
Jing Zhou;K. Hara;M. Inoue;S. Hamada;H. Yasuda;H. Moriyama;H. Endo;K. Hirota;K. Yonezawa;M. Nagata;K. Yokono
低氧诱导转录因子1（HIF-1）由HIF-1 α和HIF-1 β亚基组成，调节参与响应低氧的多种适应性过程的多种基因的表达。虽然氧可用性通过蛋白水解降解调节HIF-1 α，但一些生长因子通过蛋白质合成调节HIF-1 α，部分通过哺乳动物雷帕霉素靶蛋白复合物1（TORC 1）途径。我们在此报告的作用，营养物质的可利用性的调节HIF-1。葡萄糖而不是氨基酸的可用性降低，导致HIF 1依赖性基因和HIF-1 α蛋白在缺氧反应中的表达降低。HIF-1 α mRNA的表达没有被显著抑制，并且DMOG（HIF-1 α的蛋白酶体降解的抑制剂）在缺氧结合葡萄糖消耗下没有诱导HIF-1 α蛋白的表达。与葡萄糖存在下的作用相比，缺氧条件下的葡萄糖消耗诱导AMP依赖性激酶途径的更强激活和eIF 2 α的磷酸化，以及TORC 1途径的几乎完全抑制。这些发现意味着在缺氧条件下葡萄糖的可用性降低部分地通过抑制HIF-1 α mRNA翻译来下调HIF-1，这偶尔在病理生理学情况如缺血性疾病中观察到。
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.