Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function.

The p53 tumor suppressor is maintained at low levels in normal cells by Mdm2-mediated degradation and strongly stabilized in response to various types of stress including hypoxia. Although hypoxia-inducible factor 1 alpha (HIF-1 alpha) has been implicated to be involved in p53 stabilization, the precise mechanism by which HIF-1 alpha ...
regulates p53-mediated function remains unknown. Here, we found that HIF-1 alpha directly binds Mdm2 both in vitro and in vivo; in contrast, p53 fails to directly interact with HIF-1 alpha in vitro. Interestingly, Mdm2 expression can significantly enhance the in vivo association between p53 and HIF-1 alpha, indicating that Mdm2 may act as a bridge and mediate the indirect interaction between HIF-1 alpha and p53 in cells. Furthermore, HIF-1 alpha protects p53 degradation mediated by Mdm2, and leads to activation of p53-mediated transcription in cells. To elucidate the mechanism of HIF-1 alpha-mediated effect, we also found that HIF-1 alpha can significantly suppress Mdm2-mediated p53 ubiquitination in vitro and blocks Mdm2-mediated nuclear export of p53. These results have significant implications regarding the molecular mechanism by which p53 is activated by HIF-1 alpha in response to hypoxia.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Anoxia, Blotting, Western, Cell Nucleus, Cells, Cultured, Glutathione Transferase, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Luciferases, Mice, Nuclear Proteins, Plasmids, Precipitin Tests, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Transcription Factors, Transfection, Tumor Cells, Cultured, Tumor Suppressor Protein p53
J. Biol. Chem.
Date: Apr. 18, 2003
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