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

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.

Pubmed ID: 9697772

Authors

  • Carmeliet P
  • Dor Y
  • Herbert JM
  • Fukumura D
  • Brusselmans K
  • Dewerchin M
  • Neeman M
  • Bono F
  • Abramovitch R
  • Maxwell P
  • Koch CJ
  • Ratcliffe P
  • Moons L
  • Jain RK
  • Collen D
  • Keshert E
  • Keshet E

Journal

Nature

Publication Data

July 30, 1998

Associated Grants

  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Animals
  • Apoptosis
  • CHO Cells
  • Cell Division
  • Cell Hypoxia
  • Cell Line
  • Cricetinae
  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • Gene Targeting
  • Glucose
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lymphokines
  • Mice
  • Mice, Nude
  • Neoplasms, Experimental
  • Neovascularization, Pathologic
  • Nuclear Proteins
  • Oxygen
  • Regional Blood Flow
  • Stem Cells
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors