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J. Biol. Chem. Apr (2003); 278(16):13595-8
Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function.
Chen D, Li M, Luo J, Gu W
Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Abstract: 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.
[PUBMED: 12606552] Download Biogrid Interactions in a variety of formats including PSI FormatPUBMED
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Chris Stark, Bobby-Joe Breitkreutz, Teresa Reguly, Lorrie Boucher, Ashton Breitkreutz, Mike Tyers.
Nucleic Acids Res. Jan 1;34:D535-9.