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. 1998 Jul 30;394(6692):485-90.
doi: 10.1038/28867.

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

P Carmeliet  1 , Y Dor, J M Herbert, D Fukumura, K Brusselmans, M Dewerchin, M Neeman, F Bono, R Abramovitch, P Maxwell, C J Koch, P Ratcliffe, L Moons, R K Jain, D Collen, E Keshert
Affiliations

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

P Carmeliet et al. Nature. .

Erratum in

  • Nature 1998 Oct 1;395(6701):525. Keshet E [corrected to Keshert E]

Abstract

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.

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