The role of p53 in apoptosis.
The dynamic and multiple functions of p53, together with its involvement in the most common non-infectious diseases, underscore the need to elucidate the complexity of the p53 regulatory networks. Pathological conditions such as cancer, neurodegeneration, ischemia, cholestasis, and atherosclerosis are all strongly associated with deregulated levels of apoptosis in which p53 dysfunction has a prominent role. We will highlight recent developments of p53-induced apoptosis in human diseases, with a focus on modulation of liver cell apoptosis. In addition, we will discuss controversies arising from widespread p53 activation as a therapeutic approach to cancer. Recent studies have provided relevant and unprecedented information about mechanistic antiapoptotic functions of the endogenous bile acid, ursodeoxycholic acid (UDCA), suggesting that the finely tuned, complex control of p53 by Mdm-2 (mouse double minute-2, an oncoprotein) is a key step in UDCA modulation of p53-triggered apoptosis. We will also review recent therapeutic strategies and clinical applications of targeted agents, their safety, and efficacy, with particular emphasis on potential benefits of UDCA.
Amaral
Joana D
JD
Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
Xavier
Joana M
JM
Steer
Clifford J
CJ
Rodrigues
Cecília M
CM
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D050197:Atherosclerosis / Q000473:pathology; D001647:Bile Acids and Salts / Q000378:metabolism; D015195:Drug Design; D016158:Genes, p53; D006801:Humans; D007511:Ischemia / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D016159:Tumor Suppressor Protein p53; D014580:Ursodeoxycholic Acid