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.
Chen
Delin
D
Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Li
Muyang
M
Luo
Jianyuan
J
Gu
Wei
W
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase