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

Carmeliet, P; Dor, Y; Herbert, JM; Fukumura, D; Brusselmans, K; Dewerchin, M; ... Keshet, E; + view all (1998) Role of HIF-1 alpha or in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. NATURE , 394 (6692) 485 - 490.

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Abstract

As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced(1). Hypoxia-inducible factor (KIF)-1 alpha helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis(2-4). Here we show that hypoxia and hypoglycaemia reduce proliferation and increase apoptosis in wild-type (HIF-1 alpha(+/+)) embryonic stem (ES) cells, but not in ES cells with inactivated HIF-1 alpha. genes (HIF-1 alpha(-/-)); however, a deficiency of HIF-1 alpha does not affect apoptosis induced by cytokines. We find that hypoxia/hypoglycaemia-regulated genes involved in controlling the cell cycle are either HIF-1 alpha-dependent (those encoding the proteins p53, p21, Bcl-2) or HLF-1 alpha-independent (p27, GADD153), suggesting that there are at least two different adaptive responses to being deprived of oxygen and nutrients, Loss of HIF-1 alpha. 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-1 alpha. 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(1,5), this new role for HIF-1 alpha in hypoxic control of cell growth and death may be of general pathophysiological importance.

Type:Article
Title:Role of HIF-1 alpha or in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis
Keywords:GLUCOSE-REGULATED PROTEINS, INDUCIBLE FACTOR-1, ARREST, P21
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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