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Inhibiting the p53–MDM2 interaction: an important target for cancer therapy

Key Points

  • The tumour suppressor p53 induces cell death by apoptosis in response to various stress conditions, such as oncogene activation or DNA damage.

  • The loss of p53 tumour-suppressor activity — either by mutation/deletion of the TP53 gene or by inhibition of the p53 protein — favours the development of cancer.

  • The MDM2 protein is a negative regulator of p53. After binding to p53, it inhibits its transcriptional activity, favours its nuclear export and stimulates its degradation.

  • The overexpression of MDM2 in various tumours inhibits p53, therefore favouring uncontrolled cell proliferation.

  • The inhibition of the p53–MDM2 interaction is an attractive strategy to activate p53-mediated apoptosis in tumours with overexpressed MDM2, but wild-type p53.

  • Several low-molecular-weight compounds and peptides that inhibit the p53–MDM2 interaction have been obtained. The peptidic inhibitors show an antiproliferative effect in tumour cells overexpressing MDM2.

Abstract

p53 is an attractive therapeutic target in oncology because its tumour-suppressor activity can be stimulated to eradicate tumour cells. Inhibiting the p53–MDM2 interaction is a promising approach for activating p53, because this association is well characterized at the structural and biological levels. MDM2 inhibits p53 transcriptional activity, favours its nuclear export and stimulates its degradation, so inhibiting the p53–MDM2 interaction with synthetic molecules should lead to p53-mediated cell-cycle arrest or apoptosis in p53-positive stressed cells.

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Figure 1: The p53-mediated response.
Figure 2: Regulation of p53 by MDM2.
Figure 3: Structure of the p53–MDM2 complex.

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DATABASES

LocusLink

CDKN1A

Mdm2

MDM2

MDMX

MYC

p53

RAS

TP63

TP73

Trp53

Trp63

Trp73

FURTHER INFORMATION

MDM2 database

p53 home page

Structure of p53–MDM2

Glossary

NUCLEAR MAGNETIC RESONANCE

(NMR). A technique that uses the magnetic properties of certain atomic nuclei (such as 1H, 13C and 15N) to determine the structure of the proteins.

X-RAY CRYSTALLOGRAPHY

A technique that uses the diffraction of the X-rays to determine the structure of the proteins.

PHAGE DISPLAY

A technology that is used for displaying a protein (or peptide) on the surface of a bacteriophage, which contains the gene(s) that encodes the displayed protein(s), thereby physically linking the genotype and phenotype.

IC50

The concentration of an inhibitor that is required to inhibit 50% of the p53–MDM2 interaction.

AIB

(α-amino isobutyric acid). A non-natural amino acid that is used to favour helical conformations in peptides.

AC3C

(1-amino-cyclopropanecarboxylic acid). A non-natural amino acid that is used to stabilize 310-helix conformations in peptides.

PMP

(Phosphonomethylphenylalanine). A tyrosine substituted at its hydroxyl group by a phosphonomethyl moiety.

6CLTRP

(6-chloro-tryptophan). Tryptophan with a chlorine at position-6 (corresponds to Cη2).

ELISA

(Enzyme-linked immunosorbent assay). A solid-phase immunoassay that detects the interaction between proteins and specific antibodies.

FACS

(Fluorescence-activated cell sorting). A technique that is used in flow cytometry to detect cells that are labelled with fluorescent dyes.

TUNEL

(TdT-mediated dUTP-X nick-end labelling). A method that is used to measure DNA strand breaks during apoptosis.

E6 PROTEIN

A viral oncoprotein that is derived from certain human papillomavirus types that are associated with increased risk of cervical cancer. E6 binds to and targets p53 for ubiquitin-mediated degradation.

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Chène, P. Inhibiting the p53–MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer 3, 102–109 (2003). https://doi.org/10.1038/nrc991

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