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

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Although hypoxia (lack of oxygen in body tissues) is perhaps the most physiological inducer of the wild-type p53 gene [1], the mechanism of this induction is unknown. Cells may detect low oxygen levels through a haem-containing sensor protein [2]. The hypoxic state can be mimicked by using cobalt chloride and the iron chelator desferrioxamine [2-5]: like hypoxia, cobalt chloride and desferrioxamine activate hypoxia-inducible factor 1 alpha (HIF-1 alpha) [6], which stimulates the transcription of several genes that are associated with hypoxia [6-9]. Here we show that these treatments induce accumulation of wild-type p53 through HIF-1 alpha-dependent stabilization of p53 protein. Induction of p53 does not occur in either a mutant hepatoma cell line that is unable to induce HIF-1 alpha [10] or embryonic stem cells derived from mice lacking HIF-1 beta [11]. HIF-1 alpha 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-1 alpha and wild-type p53 also contain p53. Transfection of normoxic MCF7 cells with HIF-1 alpha stimulates a co-transfected p53-dependent reported 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-1 alpha.

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