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

Peter Carmeliet*, Yuval Dor, Jean Marc Herber, Dai Fukumura, Koen Brusselmans, Mieke Dewerchin, Michal Neeman, Françoise Bono, Rinat Abramovitch, Patrick Maxwell, Cameron J. Koch, Peter Ratcliffe, Lieve Moons, Rakesh K. Jain, Désiré Collen, Eli Keshet

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2288 Scopus citations

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 HIF1α-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.

Original languageAmerican English
Pages (from-to)485-490
Number of pages6
JournalNature
Volume394
Issue number6692
DOIs
StatePublished - 30 Jul 1998

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