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Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis

机译:HIF-1α在缺氧介导的细胞凋亡,细胞增殖和肿瘤血管生成中的作用

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As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced. Hypoxia-inducible factor (HIF)-1α 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-1α~(+/+)) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1α genes (HIF-1α~(-/-)); however, a deficiency of HIF-1α does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1α-dependent (those encoding the proteins p53, p21, Bcl-2) or HIF-1α-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients, Loss of HIF-1α 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-1α 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-1α in hypoxic control of cell growth and death may be of general pathophysiological importance.
机译:由于缺氧(缺氧)和营养,细胞的生长和活力降低。缺氧诱导因子(HIF)-1α通过诱导糖酵解,促红细胞生成和血管生成来帮助恢复氧稳态。在此我们发现低氧和低血糖会降低野生型(HIF-1α〜(+ / +))胚胎干(ES)细胞的增殖并增加其凋亡,而在具有灭活的HIF-1α基因(HIF-1α〜 (-/-));但是,HIF-1α的缺乏不会影响细胞因子诱导的凋亡。我们发现参与控制细胞周期的低氧/低血糖调节基因是HIF-1α依赖性的(编码蛋白质p53,p21,Bcl-2的基因)或HIF-1α依赖性的(p27,GADD153),这表明是对缺氧和养分的至少两种不同的适应性反应,HIF-1α的丢失减少了低氧诱导的血管内皮生长因子的表达,防止了ES衍生肿瘤中大血管的形成,并损害了血管功能,从而导致缺氧肿瘤块内的微环境。然而,由于缺氧诱导的细胞凋亡减少和应激诱导的增殖增加,HIF-1α肿瘤的生长并未受到阻碍而是被加速了。由于低氧应激会导致许多(病理)生物学疾病,因此HIF-1α在低氧控制细胞生长和死亡中的新作用可能具有一般的病理生理学重要性。

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