Key Points
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In vitro and transfection studies have suggested a p53 regulation model that emphasizes the importance of phosphorylation to produce structural changes in p53 to enable competition between MDM2 and p300 for binding the N-terminal p53 transactivation domain and inducing competing modifications in the p53 C-terminal regulatory domain. In unstressed cells, MDM2 binding in the N terminus would inhibit p53 activity and the MDM2-mediated ubiquitylation of the C terminus would promote p53 degradation; after stress, the phosphorylation of the p53 N terminus increases p300 binding, and the p300-mediated acetylation of the C terminus stabilizes and activates p53.
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The above model is not supported by recent in vivo studies, because mouse mutants that express different point mutations in the N terminus and C terminus of p53 do not have the predicted phenotypes. Analysis of mutations found in human tumours also suggest that modifiable serine, threonine and lysine residues in the N-terminal and C-terminal domains do not provide on–off switches for p53.
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Recent mouse mutants confirm the importance of MDM2 in p53 regulation, and show the separate contribution of the MDM2-related protein, MDM4 (also called MDMX) for p53 regulation: in vivo data now indicate that MDM2 mainly regulates p53 stability, whereas MDM4 contributes significantly to regulating p53 activity. These and other data suggest that a switch from MDM2 degradation of p53 to degradation of itself and MDM4 is responsible for p53 accumulation and activation after stress.
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These results indicate the importance of developing drugs that antagonize MDM2–p53 and MDM4–p53 interactions. Candidate MDM2 antagonists have been developed, but not MDM4 antagonists.
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Importantly, MDM2 and MDM4 antagonists could cooperate to activate p53 in two to three million patients diagnosed with cancer each year.
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As p53, MDM2 and MDM4 interact with many proteins, further analyses of these interactions might also lead to new and broadly useful anticancer strategies.
Abstract
Mutations in TP53, the gene that encodes the tumour suppressor p53, are found in 50% of human cancers, and increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest. Understanding p53 regulation remains a crucial goal to design broadly applicable anticancer strategies based on this pathway. This Review of in vitro studies, human tumour data and recent mouse models shows that p53 post-translational modifications have modulatory roles, and MDM2 and MDM4 have more profound roles for regulating p53. Importantly, MDM4 emerges as an independent target for drug development, as its inactivation is crucial for full p53 activation.
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Acknowledgements
We thank Mark Wade for critical comments on the manuscript. We would like to apologize for the many studies that could not be cited in the present review due to space constraints. Please refer to the review by Bode and Dong (reference 10) for earlier references on p53 post-translational modifications, to the review by Momand et al. (reference 7) for early evidence of MDM2 gene amplification in tumours, and to the BIND and HPRD databases (Table 3) for more references on proteins that interact with p53, MDM2 and MDM4. Also, we acknowledge the functional and clinical importance of the numerous p53 target genes (reviewed in references 1,2), but were unable to discuss them in detail here, again due to space constraints.
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Human Protein Reference Database
Glossary
- Prolyl isomerase
-
An enzyme that catalyses the cis-trans interconversion of prolines in specific amino-acid motifs. For example, PIN1 binds to motifs containing a phosphorylated serine or threonine preceding a proline, and catalyses the isomerization of the proline residue.
- Sumoylation
-
Conjugation with a small ubiquitin-like modifier protein (SUMO) of one or several lysines within the protein, which might regulate protein function. The 3D structure of SUMO1 is very similar to that of ubiquitin, although they share only 18% amino-acid sequence identity.
- Neddylation
-
Conjugation with NEDD8 (neural precursor cell expressed developmentally downregulated 8) of one or several lysines within the protein, which might regulate protein function. NEDD8 is an 81 amino-acid protein that shares 60% amino-acid sequence identity with ubiquitin.
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Toledo, F., Wahl, G. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6, 909–923 (2006). https://doi.org/10.1038/nrc2012
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DOI: https://doi.org/10.1038/nrc2012
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