Journal of Biological Chemistry
Volume 278, Issue 16, 18 April 2003, Pages 13595-13598
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Direct Interactions between HIF-1α and Mdm2 Modulate p53 Function*

https://doi.org/10.1074/jbc.C200694200Get rights and content
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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 1α (HIF-1α) has been implicated to be involved in p53 stabilization, the precise mechanism by which HIF-1α regulates p53-mediated function remains unknown. Here, we found that HIF-1α directly binds Mdm2 both in vitro andin vivo; in contrast, p53 fails to directly interact with HIF-1α in vitro. Interestingly, Mdm2 expression can significantly enhance the in vivo association between p53 and HIF-1α, indicating that Mdm2 may act as a bridge and mediate the indirect interaction between HIF-1α and p53 in cells. Furthermore, HIF-1α protects p53 degradation mediated by Mdm2, and leads to activation of p53-mediated transcription in cells. To elucidate the mechanism of HIF-1α-mediated effect, we also found that HIF-1α 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-1α in response to hypoxia.

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Leukemia & Lymphoma Society Scholar.

Published, JBC Papers in Press, February 26, 2003, DOI 1074/jbc.C200694200

*

This work was supported in part by grants from the Leukemia & Lymphoma Society, Avon Foundation, the Stewart Trust, the Irma T. Hirschl Trust, and National Institutes of Health/NCI (to W. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.