Abstract
Cells exposed to oxygen deprivation in vitro have been shown to reduce proliferation and/or engage in programmed cell death. There is considerable controversy in the literature as to the role of hypoxia-inducible factor-1 (HIF-1) and HIF-1 target genes in initiating these responses. We therefore examined the oxygen dependence and the role of the hypoxia-responsive transcription factor HIF-1 in making the cellular death decision. Oxygen concentrations as low as 0.5% did not alter the growth of HIF-1-proficient or HIF-1-deficient murine fibroblasts, or human tumor cells, despite the appropriate induction of HIF-1 target genes. Severe hypoxia (<0.01% oxygen) did induced apoptosis, resulting in decreased colony formation, chromatin condensation, DNA fragmentation, and caspase activation but also independent of HIF1alpha status. Transcriptional induction of HIF-1-dependent genes putatively involved in cell death like BNip3 and BNip3L was therefore disassociated from hypoxia-dependent toxicity. Likewise, forced overexpression of a nondegradable form of HIF-1alpha in several human tumor cell lines was not sufficient to induce apoptosis under normoxic conditions. Taken together, these findings indicate that additional molecular events are triggered by anoxia in a HIF-1-independent manner, and these changes are necessary for cell death observed in low-oxygen environments.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology*
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Cell Hypoxia / physiology*
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Fibroblasts / cytology
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Fibroblasts / metabolism
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HeLa Cells
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Membrane Proteins / physiology
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Mice
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Mice, Knockout
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology*
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Oxygen / metabolism*
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology
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Transcription Factors / biosynthesis
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
Substances
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BNIP3 protein, human
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BNIP3L protein, human
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DNA-Binding Proteins
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Oxygen