Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α
Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α
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DOI：
10.1101/gad.12.2.149
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发表时间：
1998-01-15
影响因子：
10.5
通讯作者：
Semenza, GL
中科院分区：
文献类型：
--
作者：
Iyer, NV;Kotch, LE;Semenza, GL
缺氧是一种重要的发育和生理刺激，在癌症、心脏病发作、中风和其他主要死亡原因的病理生理学中起关键作用。缺氧诱导因子1（HIF-1）是唯一已知的哺乳动物转录因子表达独特的生理相关水平的缺氧。我们现在报道，在不表达O-2调节的HIF-1 α亚基的HIF-1 α（-/-）胚胎干细胞中，编码葡萄糖转运蛋白和糖酵解酶的mRNA水平降低，细胞增殖受损。缺氧Hif 1 α（-/-）胚胎干细胞和囊状胚体中血管内皮生长因子mRNA表达也明显降低。HIF-1 α的完全缺乏导致Hif 1 α（-/-）胚胎的发育停滞和E11的致死性，表现为神经管缺陷、心血管畸形和头部间充质内的显著细胞死亡。在HIF 1 α（+/+）胚胎中，HIF-1 α表达在E8.5和E9.5之间增加，与HIF 1 α（-/-）胚胎中发育缺陷和细胞死亡的发生一致。这些结果表明，HIF-1 α是细胞和发育O-2稳态的主要调节因子。
Hypoxia is an essential developmental and physiological stimulus that plays a key role in the pathophysiology of cancer, heart attack, stroke, and other major causes of mortality. Hypoxia inducible factor 1 (HIF-1) is the only known mammalian transcription factor expressed uniquely in response to physiologically relevant levels of hypoxia. We now report that in Hif1 alpha(-/-) embryonic stem cells that did not express the O-2-regulated HIF-1 alpha subunit, levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. Vascular endothelial growth factor mRNA expression was also markedly decreased in hypoxic Hif1 alpha(-/-) embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1 alpha resulted in developmental arrest and lethality by E11 of Hif1 alpha(-/-) embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. In Hif1 alpha(+/+) embryos, HIF-1 alpha expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death in Hif1 alpha(-/-)embryos. These results demonstrate that HIF-1 alpha is a master regulator of cellular and developmental O-2 homeostasis.