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

Peter Carmeliet (), Yuval Dor, Jean-Marc Herbert, 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 and Eli Keshet
Additional contact information
Peter Carmeliet: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology
Yuval Dor: Hebrew University-Hadassah Medical School
Jean-Marc Herbert: Sanofi Recherche
Dai Fukumura: Massachusetts General Hospital and Harvard Medical School
Koen Brusselmans: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology
Mieke Dewerchin: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology
Michal Neeman: Weizmann Institute of Science
Françoise Bono: Sanofi Recherche
Rinat Abramovitch: Weizmann Institute of Science
Patrick Maxwell: Institute of Molecular Medicine, John Radcliffe Hospital, Wellcome Trust Centre for Human Genetics
Cameron J. Koch: School of Medicine, University of Pennsylvania
Peter Ratcliffe: Institute of Molecular Medicine, John Radcliffe Hospital, Wellcome Trust Centre for Human Genetics
Lieve Moons: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology
Rakesh K. Jain: Massachusetts General Hospital and Harvard Medical School
Désiré Collen: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology
Eli Keshet: Hebrew University-Hadassah Medical School

Nature, 1998, vol. 394, issue 6692, 485-490

Abstract: Abstract As a result of deprivation of oxygen (hypoxia) and nutrients, the growth and viability of cells is reduced1. Hypoxia-inducible factor(HIF)-1α helps to restore oxygen homeostasis by inducing glycolysis, erythropoiesis and angiogenesis2,3,4. 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 disorders1,5, this new role for HIF-1α in hypoxic control of cell growth and death may be of general pathophysiological importance.

Date: 1998
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DOI: 10.1038/28867

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