Key Points
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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.
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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.
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Different stimuli induce p53 with different kinetics, which is reflected in the diversity of responses to p53.
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Variation is coordinated by post-translational modifications of p53 and the availability of cofactors that together determine the appropriate cellular fate.
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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.
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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.
Abstract
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.
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We thank the Ludwig Institute for Cancer Research, the Association for International Cancer Research and the European Union for funding, and G. Bond for critical reading of the manuscript.
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Glossary
- Senescence
-
The irreversible arrest of cell growth. This process limits the lifespan of mammalian cells and prevents the growth of cells that are at risk of neoplastic transformation.
- Missense mutation
-
A genetic mutation whereby a single nucleotide is substituted, which changes a codon so that it codes for a different amino acid. This change in one amino acid can alter the activity of the protein.
- Telomere erosion
-
The shortening of the ends of telomeres due to incomplete replication of the lagging strand of DNA. The shortening of telomeres can happen in the early stages of cancer, leading to short dysfunctional telomeres.
- γ-radiation
-
A type of electromagnetic radiation that is generally characterized by having high frequency and energy, but short wavelength. γ-radiation is often used to kill living cells, such as in the sterilization of medical equipment, in a process called irradiation.
- Poly-ubiquitylation
-
The addition of multiple ubiquitin molecules to a target protein. The process usually involves the addition of a chain of ubiquitin to a target Lys residue (or residues) on the target protein.
- E3 ligase
-
The third enzyme in a series (after E1 and E2) of enzymes that mediate the ubiquitylation of target proteins. E3 ligases recruit E2 ligases and the specific substrate, and aid in the transfer of ubiquitin to the target protein.
- Co-activator
-
A protein that enhances gene expression by binding (directly or indirectly) to a transcription factor.
- Mono-ubiquitylation
-
The addition of a single ubiquitin molecule to a target Lys residue on the substrate protein.
- Poly(ADP-ribosyl)ation
-
The covalent or non-covalent attachment of polymers of ADP-ribose units to proteins. Poly(ADP-ribose) polymerase-1 (PARP1) catalyses the covalent poly(ADP-ribosyl)ation of p53
- Prolyl isomerase
-
A molecule that mediates the interconversion of Pro residues in specific amino-acid motifs from the cis to the trans conformation, and vice versa.
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Murray-Zmijewski, F., Slee, E. & Lu, X. A complex barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol 9, 702–712 (2008). https://doi.org/10.1038/nrm2451
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DOI: https://doi.org/10.1038/nrm2451
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