| Ursodeoxycholic acid modulates the ubiquitin-proteasome degradation pathway of p53. | |
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MedLine Citation:
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PMID: 20807506 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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p53/Mdm-2 interaction is a prime target of ursodeoxycholic acid (UDCA) for regulating apoptosis in primary rat hepatocytes. Here, we further explored the role of UDCA in downregulating p53 by Mdm-2. UDCA reduced the stability of p53 by decreasing protein half-life. Although proteasomal activity was slightly increased with UDCA, the effect was also observed for other bile acids. More importantly, immunoprecipitation assays revealed that UDCA promoted p53 ubiquitination, therefore leading to increased p53 degradation. In this regard, proteasome inhibition after UDCA pre-treatment resulted in accumulation of ubiquitinated p53, which in turn was prevented in cells overexpressing a mutated form of p53 that does not undergo Mdm-2 ubiquitination. The involvement of Mdm-2 in UDCA-mediated response was further confirmed by siRNA-mediated gene silencing experiments. Finally, the protective effect of UDCA against p53-induced apoptosis was abolished after inhibition of proteasome activity and prevention of p53 ubiquitination by Mdm-2. These findings suggest that UDCA protects cells from p53-mediated apoptosis by promoting its degradation via the Mdm-2-ubiquitin-proteasome pathway. |
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Authors:
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Joana D Amaral; Rui E Castro; Susana Solá; Clifford J Steer; Cecília M P Rodrigues |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-31 |
Journal Detail:
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Title: Biochemical and biophysical research communications Volume: 400 ISSN: 1090-2104 ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-04 Completed Date: 2010-11-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372516 Medline TA: Biochem Biophys Res Commun Country: United States |
Other Details:
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Languages: eng Pagination: 649-54 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon 1649-003, Portugal. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Cells, Cultured Cytoprotection* Half-Life Hepatocytes / drug effects*, metabolism Proteasome Endopeptidase Complex / metabolism* Proto-Oncogene Proteins c-mdm2 / metabolism Rats Tumor Suppressor Protein p53 / metabolism* Ubiquitin / metabolism* Ubiquitination / drug effects Ursodeoxycholic Acid / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Tumor Suppressor Protein p53; 0/Ubiquitin; 128-13-2/Ursodeoxycholic Acid; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 6.3.2.19/Mdm2 protein, rat; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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