A complex barcode underlies the heterogeneous response of p53 to stress

• Published in: Nature reviews. Molecular cell biology Vol. 9; no. 9; pp. 702 - 712
• Main Authors: Lu, Xin, Murray-Zmijewski, Fiona, Slee, Elizabeth A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2008; Nature Publishing Group
• Subjects: Animals; Apoptosis; Bar codes; Biochemistry; Biomedical and Life Sciences; Cancer; Cancer Research; Cell Biology; Cell growth; Cellular signal transduction; Developmental Biology; Genes; Genetic aspects; Health aspects; Heterogeneity; Humans; Life Sciences; Medical research; Mutation; Organ Specificity; Physiology; Protein Transport; Proteins; review-article; Senescence; Stem Cells; Stress, Physiological - metabolism; Telomerase; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; United Kingdom
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm2451

Key Points The tumour suppressor p53 is a master sensor of stress and integrates incoming signals to prevent malignant progression by inducing cellular responses such as apoptosis and senescence. The response to p53 activation is heterogeneous and depends on the nature and intensity of the activating stress and on the cell or tissue type in which the stress is encountered. Different stimuli induce p53 with different kinetics, which is reflected in the diversity of responses to p53. Variation is coordinated by post-translational modifications of p53 and the availability of cofactors that together determine the appropriate cellular fate. These variables dictate the level, subcellular localization and activities of p53, whether its actions are dependent or independent of transcription, and the array of genes the expression of which are altered. Several new interacting partners of p53 have been identified, and we must now begin to understand how these partners affect p53 activity in tissue- and stress-specific contexts. The tumour suppressor p53 integrates incoming stress signals to prevent malignant progression by inducing cell responses such as apoptosis and senescence. The specific response, coordinated by p53 post-translational modifications and the availability of p53 cofactors, determines the appropriate cellular fate. The tumour suppressor p53 is activated following stress and initiates a heterogeneous response in a cell-, tissue- and stress-dependent manner. This heterogeneity is reflected in the different physiological outcomes that follow p53 activation. One mechanism that may contribute to this variability is the promoter selectivity of p53 target genes. p53 is at the hub of numerous signalling pathways that are triggered in response to particular stresses, all of which can leave their mark on p53 by way of post-translational modifications and interactions with cofactors. The precise combination of these marks, much like the bars in a barcode, dictates the behaviour of p53 in any given situation.