The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to environmental perturbations resulting in either cellular death or the maintenance of cellular homeostasis. The p53 and MDM2 proteins form a central hub in this pathway that receives stressful inputs via MDM2 and respond via p53 by informing and altering a great many other pathways and functions in the cell. The MDM2–p53 hub is one of the hubs most highly connected to other signalling pathways in the cell, and this may be why TP53 is the most commonly mutated gene in human cancers. Initial or truncal TP53 gene mutations (the first mutations in a stem cell) are selected for early in cancer development inectodermal and mesodermal-derived tissue-specific stem and progenitor cells and then, following additional mutations, produce tumours from those tissue types. In endodermal-derived tissue-specific stem or progenitor cells, TP53 mutations are functionally selected as late mutations transitioning the mutated cell into a malignant tumour. The order in which oncogenes or tumour suppressor genes are functionally selected for in a stem cell impacts the timing and development of a tumour.
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The author thanks S. Christian, N. Jenkins and N. Copeland for discussions and advice in developing this manuscript and A. Puzio-Kuter for the figures. The work presented here was supported by a programme project grant from the NIH, NCI (P01CA087497-18).
A.J.L. is the founder of a Biotech company, PMV Pharmaceuticals, which designs and produces small molecules that functionally reactivate mutant missense proteins in cancers. A.J.L. also chairs the scientific advisory board of Janssen Pharmaceuticals.
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