Journal Article

Post-translational modification of p53 in tumorigenesis

Dong, Zigang, Bode, Ann M.

2004

Overview

Key Points When a cell is confronted by stress, p53 is stabilized in the nucleus, where it initiates cellular responses through transcriptional activation or repression of distinct target genes that primarily function to prevent proliferation of damaged cells. The function of p53 is tightly controlled by its interaction with negative regulators including MDM2, which induces p53 degradation and prevents its accumulation in normal cells. This interaction can be disrupted when the cell detects DNA damage or other stresses, resulting in stabilization and activation of p53. Active p53 is subject to a diverse array of covalent post-translational modifications, which markedly influence the expression of p53 target genes. Phosphorylation and acetylation of p53 generally result in its stabilization and accumulation in the nucleus, followed by activation. Significant redundancies are observed in that the same p53 site is phosphorylated by several different protein kinases and distinct protein kinases also phosphorylate several sites on p53. Mutant p53 proteins generally show intense phosphorylation and acetylation at sites that are well known to stabilize wild-type p53, and so could facilitate accumulation of dysfunctional mutant p53 in the nucleus, where it can act as an oncogene. Overexpression of MDM2 E3 ubiquitin ligase is observed in many tumour types and results in the aberrant deactivation of p53. In normal cells, p53 post-translational modification is induced by numerous carcinogens. Evidence indicates that normal cells and cancer cells show a markedly different response to ultraviolet-light exposure. Dietary-derived chemopreventive agents induce phosphorylation of p53, resulting in cell-cycle arrest or apoptosis. These agents might have a preventive function in future anticancer therapies. Interest in the tumour suppressor p53 has generated much information regarding the complexity of its function and regulation in carcinogenesis. However, gaps still exist in our knowledge regarding the role of p53 post-translational modifications in carcinogenesis and cancer prevention. A thorough understanding of p53 will be extremely useful in the development of new strategies for treating and preventing cancer, including restoration of p53 function and selective killing of tumours with mutant TP53 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Acetylation / Acetyltransferases - physiology / Anticarcinogenic Agents - pharmacology / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinogenesis / Carcinogens - pharmacology / Cell Transformation, Neoplastic - genetics / Control / DNA - metabolism / Genes, p53 / Genetic aspects / Humans / Identification and classification / Mutation / Neoplasm Proteins - metabolism / Nuclear Proteins - metabolism / Phosphorylation / Physiological aspects / Post-translational modifications / Promyelocytic Leukemia Protein / Protein Binding / Protein Kinases - physiology / Protein Processing, Post-Translational / Protein Structure, Tertiary / review-article / Risk factors / Stress, Physiological - metabolism / Transcription Factors - metabolism / Tumor suppressor genes / Tumor Suppressor Protein p53 - metabolism / Tumor Suppressor Protein p53 - physiology / Tumor Suppressor Protein p53 - radiation effects / Tumor Suppressor Proteins / Ubiquitin - metabolism / Ultraviolet Rays