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Stabilization of wild-type p53 by hypoxia-inducible factor 1α

Nature volume 392, pages 405–408 (1998)Cite this article

Abstract

Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the wild-type p53 gene1, the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein2. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine2,3,4,5: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1α (HIF-1α) (ref. 6), which stimulates the transcription of several genes that are associated with hypoxia6,7,8,9. Here we show that these treatments induce accumulation of wild-type p53 through HIF-1α-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1α (ref. 10) or embryonic stem cells derived from mice lacking HIF-1β (ref. 11). HIF-1α is found in p53 immunoprecipitates from MCF7 cells that express wild-type p53 and are either hypoxic or have been exposed to desferrioxamine. Similarly, anti-haemagglutinin immunoprecipitates from lysates of normoxic PC3M cells that had been co-transfected with haemagglutinin-tagged HIF-1α and wild-type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1α stimulates a co-transfected p53-dependent reporter plasmid and increases the amount of endogenous p53. Our results suggest that hypoxic induction of transcriptionally active wild-type p53 is achieved as a result of the stabilization of p53 by its association with HIF-1α.

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Figure 1: Cobalt chloride and desferrioxamine cause p53 protein stabilization.
Figure 2: Induction of p53 by cobalt chloride and desferrioxamine requires concomitant induction of HIF-1α.
Figure 3: p53 and HIF-1α proteins associate directly with each other.
Figure 4: HIF-1α potentiates PG13-luciferase activity that depends on wild-type p53 (wtp53).

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Acknowledgements

We thank J. Trepel and O. Hankinson for cell lines, and B. Vogelstein and D.Livingston for plasmids and antibodies.

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Authors and Affiliations

  1. Department of Cell and Cancer Biology, Medicine Branch, NCI, NIH, Bethesda, 20892, Maryland, USA

    Won G. An, Meera Kanekal & Mikhail V. Blagosklonny

  2. Departments of Medicine and Molecular Genetics and Cell Biology,

    M. Celeste Simon

  3. Department of Pathology, Howard Hughes Medical Institute, University of Chicago, Chicago, 60637, Illinois, USA

    Emin Maltepe

  4. Medicine Branch, NCI, NIH, Key West Facility, 9610 Medical Center Drive, Room 300, Rockville, 20850, Maryland, USA

    Leonard M. Neckers

Authors
  1. Won G. An
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  2. Meera Kanekal
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Correspondence to Leonard M. Neckers.

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An, W., Kanekal, M., Simon, M. et al. Stabilization of wild-type p53 by hypoxia-inducible factor 1α. Nature 392, 405–408 (1998). https://doi.org/10.1038/32925

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