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

P Carmeliet, Y Dor, JM Herbert, D Fukumura… - Nature, 1998 - nature.com
P Carmeliet, Y Dor, JM Herbert, D Fukumura, K Brusselmans, M Dewerchin, M Neeman
Nature, 1998nature.com
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 …
Abstract
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.
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