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

Won G. An, Meera Kanekal, M. Celeste Simon, Emin Maltepe, Mikhail V. Blagosklonny and Leonard M. Neckers ()
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Won G. An: Medicine Branch
Meera Kanekal: Medicine Branch
M. Celeste Simon: Departments of Medicine and Molecular Genetics and Cell Biology
Emin Maltepe: Howard Hughes Medical Institute, University of Chicago
Mikhail V. Blagosklonny: Medicine Branch
Leonard M. Neckers: Medicine Branch, NCI, NIH, Key West Facility

Nature, 1998, vol. 392, issue 6674, 405-408

Abstract: 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.

Date: 1998
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DOI: 10.1038/32925

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