Key Points
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Activation of the transcription factor p53 in response to different types of cellular stress can lead to cell survival as well as cell elimination.
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Novel insights into the functions of p53 reveal that diverse mechanisms influence cell fate decisions upon p53 activation.
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p53 sustains metabolic health and homeostasis by allowing cells to adapt to transient metabolic and nutrient stress through the regulation of signalling pathways and by modulating transcription or the activity of metabolic enzymes.
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Basal levels of reactive oxygen species (ROS) are important for normal cellular processes, whereas excessive levels of ROS are deleterious. p53 promotes antioxidant activity under normal conditions to protect cells from ROS and promotes pro-oxidant activity under severe oxidative stress to eliminate damaged cells by inducing ROS.
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The survival functions of p53 may help to prevent tumour development, but persistence of these activities during malignant development may help to support cancer progression.
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To use manipulations of p53 activity in a therapeutic setting, whether for tumour suppression or in other pathologies, the context-dependent variability in the outcome of p53 activation needs to be carefully considered.
Abstract
The function of p53 as a tumour suppressor has been attributed to its ability to promote cell death or permanently inhibit cell proliferation. However, in recent years, it has become clear that p53 can also contribute to cell survival. p53 regulates various metabolic pathways, helping to balance glycolysis and oxidative phosphorylation, limiting the production of reactive oxygen species, and contributing to the ability of cells to adapt to and survive mild metabolic stresses. Although these activities may be integrated into the tumour suppressive functions of p53, deregulation of some elements of the p53-induced response might also provide tumours with a survival advantage.
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Acknowledgements
The authors thank K. Ryan and O. Maddocks for comments on the manuscript, and they apologize for failing to adequately reference the many important studies that have contributed to the understanding of p53. Their work is funded by Cancer Research UK (grant C596/A10419) and the European Research Council (grant 322842 METABOp53).
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Glossary
- BCL-2 family proteins
-
A group of proteins characterized by the presence of one or more BCL-2 homology (BH) domains that regulate mitochondrial outer membrane permeabilization through both pro-apoptotic and anti-apoptotic family members.
- BH3-only proteins
-
A subclass of BCL-2 family proteins that only contain a BCL-2 homology 3 (BH3) domain.
- Ceramide
-
A lipid comprising sphingosine and a fatty acyl chain that is concentrated in cell membranes. In addition to a structural role, ceramide has various signalling functions, including the ability to induce apoptosis.
- Glycolysis
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A cytoplasmic metabolic pathway that converts glucose into pyruvate through a range of enzymatic reactions.
- Tricarboxylic acid cycle
-
(TCA cycle). A mitochondrial cycle that utilizes metabolites derived from sugar, protein and fat to provide anabolic intermediates and the reducing agents NADH and FADH2 for ATP production through oxidative phosphorylation.
- Pentose phosphate pathway
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(PPP). A pathway that produces ribose sugars and NADPH from glucose and that is important for redox balance and anabolism.
- Oncocytomas
-
Usually benign tumours composed of oncocytes with granular, eosinophilic cytoplasm.
- Glutathione (GSH) tripeptide
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Consists of cysteine, glutamate and glycine and functions as an important intracellular antioxidant.
- Mitophagy
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A selective form of autophagy that targets the mitochondria; it is generally thought to help to maintain cell health by removing damaged mitochondria.
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Kruiswijk, F., Labuschagne, C. & Vousden, K. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 16, 393–405 (2015). https://doi.org/10.1038/nrm4007
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DOI: https://doi.org/10.1038/nrm4007
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