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

An Erratum to this article was published on 01 October 1998

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.

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Figure 1: Targeting of the HIF-1α gene.
Figure 2: Vascularization of HIF-1α−/− and rHIF-1α+/+ tumours.
Figure 3: Functional vascularization and growth of HIF-1α−/− and rHIF-1α+/+ tumours.

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Acknowledgements

We thank D. Livingston for monoclonal HIF-1α antibodies; M. Lampugnani and E.Dejana for CD31 antibodies; E. M. Lord for ALK3.51 antibodies; G. Suske for Sp1 antibodies; S.Plaisance and G. Theilmeier for discussion and for their help; K. Bijnens, A. Bouché, I. Cornelissen, M.De Mol, E. Gils, B. Hermans, S. Jansen, L. Kieckens, A. Manderveld, T. Vancoetsem, A. Vandenhoeck, A. Van den Boomen, P. Van Wesemael, S. Wyns (Leuven), A. Itin, I. Lamarche, P. Rogon, Y. Chen, J. Kahn and T.Gohongi for technical assistance; and M. Deprez for artwork. This work was supported in part by a NCI-OIG grant to R.J. and D.F.

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Correspondence to Peter Carmeliet.

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Carmeliet, P., Dor, Y., Herbert, J. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998). https://doi.org/10.1038/28867

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