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Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2003 Apr 18; Vol. 278 (16), pp. 13595-8. Date of Electronic Publication: 2003 Feb 26. - Publication Year :
- 2003
-
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.
- Subjects :
- Active Transport, Cell Nucleus
Animals
Blotting, Western
Cell Nucleus metabolism
Cells, Cultured
Glutathione Transferase metabolism
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit
Immunoblotting
Luciferases metabolism
Mice
Plasmids metabolism
Precipitin Tests
Protein Binding
Proto-Oncogene Proteins c-mdm2
Recombinant Fusion Proteins metabolism
Transfection
Tumor Cells, Cultured
Tumor Suppressor Protein p53 physiology
Nuclear Proteins
Proto-Oncogene Proteins metabolism
Transcription Factors metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 278
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12606552
- Full Text :
- https://doi.org/10.1074/jbc.C200694200