p53 Is a Key Molecular Target of Ursodeoxycholic Acid in Regulating Apoptosis

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 β1-induced p53 stabilization and apoptosis in prima...

Full description

Saved in:

Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 282; no. 47; pp. 34250 - 34259
Main Authors:	Amaral, Joana D., Castro, Rui E., Solá, Susana, Steer, Clifford J., Rodrigues, CecÁlia M.P.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 23-11-2007 American Society for Biochemistry and Molecular Biology
Subjects:	Animals Apoptosis - drug effects Apoptosis - physiology bcl-2-Associated X Protein - metabolism Bile Acids and Salts - metabolism Bile Acids and Salts - pharmacology Cell Cycle - drug effects Cell Cycle - physiology Cells, Cultured Cholagogues and Choleretics - metabolism Cholagogues and Choleretics - pharmacology Cytochromes c - metabolism DNA - metabolism Hepatocytes - cytology Hepatocytes - metabolism Male Mitochondria, Liver - metabolism Protein Binding - drug effects Protein Binding - physiology Protein Transport - drug effects Protein Transport - physiology Proto-Oncogene Proteins c-mdm2 - metabolism Rats Rats, Sprague-Dawley Transcription, Genetic - drug effects Transcription, Genetic - physiology Transforming Growth Factor beta1 - metabolism Transforming Growth Factor beta1 - pharmacology Tumor Suppressor Protein p53 - metabolism Ursodeoxycholic Acid - metabolism Ursodeoxycholic Acid - pharmacology
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 β1-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.
Bibliography:	http://www.jbc.org/ ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M704075200