P53 Is a Key Molecular Target of Ursodeoxycholic Acid in Regulating Apoptosis

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

doi:10.1074/jbc.m704075200

Abstract

p53 plays an important role in regulating expression of genes that mediate cell cycle progression and/or apoptosis. In addition, we have previously shown that the hydrophilic bile acid ursodeoxycholic acid (UDCA) prevents transforming growth factor beta1-induced p53 stabilization and apoptosis in primary rat hepatocytes. Therefore, we hypothesized that p53 may represent an important target in bile acid-induced modulation of apoptosis and cell survival. In this study we demonstrated that UDCA reduces p53 transcriptional activity, thereby preventing its ability to induce Bax expression, mitochondrial translocation, cytochrome c release, and apoptosis in primary rat hepatocytes. More importantly, bile acid inhibition of p53-induced apoptosis was associated with decreased p53 DNA binding activity. Subcellular localization of p53 was also altered by UDCA. Both events appear to be related with increased association between p53 and its direct repressor, Mdm-2. In conclusion, these results further clarify the antiapoptotic mechanism of UDCA and suggest that modulation of Mdm-2/p53 interaction is a prime target for this bile acid.

Highlights

Ursodeoxycholic acid (UDCA),5 a hydrophilic bile acid with low intrinsic toxicity, has been successfully used in the treatment of cholestatic liver diseases
We have previously demonstrated that UDCA decreases E2F-1 transcriptional activation, preventing the downstream events of transforming growth factor-␤1-induced cell death associated with murine double minute-2 (Mdm-2) degradation and p53 stabilization [6]
We have previously shown that UDCA prevented transforming growth factor-␤1-induced p53 stabilization and apoptosis in primary rat hepatocytes [6]

Summary

Introduction

Ursodeoxycholic acid (UDCA),5 a hydrophilic bile acid with low intrinsic toxicity, has been successfully used in the treatment of cholestatic liver diseases. In this study we demonstrated that UDCA reduces p53 transcriptional activity, thereby preventing its ability to induce Bax expression, mitochondrial translocation, cytochrome c release, and apoptosis in primary rat hepatocytes. Our results indicate that UDCA inhibits p53 transactivation and its DNA binding activity in hepatocytes by preventing nuclear accumulation of this tumor suppressor protein, in part, through a p53/Mdm-2 binding-dependent mechanism.

Results

Conclusion