Carmeliet P, Dor Y, Herbert J M, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch C J, Ratcliffe P, Moons L, Jain R K, Collen D, Keshert E
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium.
Nature. 1998 Jul 30;394(6692):485-90. doi: 10.1038/28867.
As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis. Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1alpha+/+) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1alpha genes (HIF-1alpha-/-); however, a deficiency of HIF-1alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients. Loss of HIF-1alpha reduces hypoxia-induced expression of vascular endothelial growth factor, prevents formation of large vessels in ES-derived tumours, and impairs vascular function, resulting in hypoxic microenvironments within the tumour mass. However, growth of HIF-1alpha tumours was not retarded but was accelerated, owing to decreased hypoxia-induced apoptosis and increased stress-induced proliferation. As hypoxic stress contributes to many (patho)biological disorders, this new role for HIF-1alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.
由于缺氧和营养物质缺乏，细胞的生长和活力会降低。缺氧诱导因子（HIF）-1α通过诱导糖酵解、红细胞生成和血管生成来帮助恢复氧稳态。我们在此表明，缺氧和低血糖会降低野生型（HIF-1α+/+）胚胎干细胞（ES细胞）的增殖并增加其凋亡，但不会影响HIF-1α基因失活的ES细胞（HIF-1α-/-）；然而，HIF-1α的缺乏并不影响细胞因子诱导的凋亡。我们发现，参与控制细胞周期的缺氧/低血糖调节基因要么是HIF-1α依赖性的（那些编码蛋白质p53、p21、Bcl-2的基因），要么是HIF-1α非依赖性的（p27、GADD153），这表明对缺氧和营养物质缺乏至少存在两种不同的适应性反应。HIF-1α的缺失会降低缺氧诱导的血管内皮生长因子表达，阻止ES来源肿瘤中大型血管的形成，并损害血管功能，导致肿瘤块内出现缺氧微环境。然而，HIF-1α缺陷型肿瘤的生长并未受到抑制，反而加速了，这是由于缺氧诱导的凋亡减少以及应激诱导的增殖增加所致。由于缺氧应激会导致许多（病理）生物学紊乱，HIF-1α在缺氧控制细胞生长和死亡方面的这一新作用可能具有普遍的病理生理学重要性。
