Key Points
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p53 is a tumour-suppressor protein that induces apoptotic cell death in response to oncogenic stress. Malignant progression is dependent on loss of p53 function, either through mutation in the TP53 gene (which encodes p53) itself or by defects in the signalling pathways that are upstream or downstream of p53.
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Mutations in TP53 occur in about half of all human cancers, almost always resulting in the expression of a mutant p53 protein that has acquired transforming activity.
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p53-induced apoptosis depends on the ability of p53 to activate gene expression, although transcriptionally independent activities of p53 can also contribute to the apoptotic response.
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The apoptotic and cell-cycle arrest activities of p53 can be separated, and apoptotic cofactors that play a specific role in allowing p53-induced death are being identified.
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Regulation of the apoptotic function of p53 is associated with selective activation of apoptotic target genes. Cofactors that specifically contribute to p53-mediated activation of apoptotic target genes include JMY, ASPP and the other p53-family members p63 and p73.
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Phosphorylation of p53 regulates its ability to activate the expression of apoptotic target genes, and other post-translational modifications such as acetylation might also have a role.
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In tumours that retain wild-type p53, the apoptotic response might be hindered by defects in the apoptotic cofactors. These, therefore, represent additional targets for the design of therapeutics that are aimed at reactivating p53-mediated apoptosis in cancer cells.
Abstract
Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.
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Acknowledgements
We apologize to all our colleagues whose excellent papers we have been unable to cite. Also, we thank the members of both the Vousden and Lu laboratories for stimulating discussion and suggestions.
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Glossary
- DOMINANT-NEGATIVE MUTANT
-
A non-functional mutant protein that competes with the normal, non-mutated protein, thereby blocking its activity.
- UBIQUITIN LIGASES
-
A family of enzymes that function in the final step of conjugation of ubiquitin chains to lysine residues in target proteins. Polyubiquitylated proteins are recognized and degraded by the proteasome.
- APC
-
(Adenomatous polyposis coli). A tumour-suppressor gene that is mutated in sporadic colorectal cancers.
- DIFFERENTIAL DISPLAY
-
An expression analysis method in which cDNAs from different samples are amplified by polymerase chain reaction using a combination of random primers and anchored oligo-dT primers.
- SAGE
-
Serial analysis of gene expression that is based on the capture and analysis of a short nucleotide sequence (or tag) that is close to the 3′ end of each cDNA in the sample.
- MICROARRAYS
-
Chips that contain arrays of oligonucleotides that correspond to known genes and that are used to analyse gene expression by hybridization with samples. In contrast to differential display and SAGE, this technique is limited to the analysis of genes that are represented on the chip.
- HUMAN PAPILLOMAVIRUS E7
-
A viral oncoprotein that is derived from certain human papillomavirus types that are associated with an increased risk of cervical cancer. E7 binds and inactivates retinoblastoma.
- PEUTZ–JEGHER SYNDROME
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A cancer-susceptibility syndrome that is associated with inheritance of mutation in LKB1, a serine/threonine kinase.
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Vousden, K., Lu, X. Live or let die: the cell's response to p53. Nat Rev Cancer 2, 594–604 (2002). https://doi.org/10.1038/nrc864
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DOI: https://doi.org/10.1038/nrc864
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