Ursodeoxycholic acid modulates the ubiquitin-proteasome degradation pathway of p53

Joana D. Amaral, Rui E. Castro, Susana Solá, Clifford J. Steer, Cecília M.P. Rodrigues

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)649-654
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume400
Issue number4
DOIs
StatePublished - Oct 1 2010

Bibliographical note

Funding Information:
We thank Dr. Toshiyuki Miyashita, National Research Institute for Child Health and Development, Tokyo, Japan, for providing wild-type pCMV-p53 and Dr. Karen Vousden, The Beatson Institute for Cancer Research, Glasgow, UK, for mutant p53ΔI plasmid. We are also grateful to Dr. Paulo Pereira, Faculty of Medicine, Coimbra, Portugal, for providing the HA-Ub construct. This work was supported by grant PTDC/SAU-GMG/099162/2008 from Fundação para a Ciência e a Tecnologia (FCT), Lisbon, Portugal. J.D.A. was recipient of postdoctoral fellowship BPD/47376/2008 from FCT.

Keywords

  • Apoptosis
  • Bile acids
  • Mdm-2
  • P53
  • Ubiquitination

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