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Rescuing the function of mutant p53

Nature Reviews Cancer volume 1, pages 68–76 (2001)Cite this article

Key Points

  • Aggressive cancers that do not respond to traditional chemotherapy regimes are often resistant owing to the lack of p53-dependent apoptosis. New therapies are being developed that aim to restore p53 tumour suppression to cancer cells.

  • 50% of cancers lose p53 function as a result of mutations that produce single amino-acid substitutions in the core DNA-binding domain. In other cancers, wild-type p53 is targeted for degradation by cellular (MDM2) or viral (E6) oncoproteins.

  • Mutant p53 is inactive for transcriptional transactivation. Cancer cells therefore accumulate mutant p53 (in the absence of MDM2) and fail to induce p53-dependent growth arrest, DNA repair or apoptosis. The mutant protein is a target for rescue by drugs that bind to the core domain to reverse the effects of mutation.

  • Mutations can reduce the DNA-binding affinity and thermodynamic stability of the core domain to varying extents, described by five mutant classes. The effect of a mutation is largely dictated by its location within the core-domain structure. Mutations in the β-sandwich induce unfolding, whereas mutations in the DNA-binding surface can have a greater effect on DNA binding.

  • The activity of certain p53 mutants can be restored by second-site suppressor mutations that introduce an additional DNA contact, correct local structural distortion or increase the stability of the core domain structure. Potential therapeutic drugs may rescue mutant p53 by the same mechanisms.

  • Small molecules, identified in a screen for protein folding, stabilize the wild-type and mutant p53 core domain, presumably by binding specifically to the native protein. Correction of mutant folding restores p53 function to cancer cells and inhibits tumour growth in mice.

  • These prototype compounds require increased potency for use at concentrations that are practical for cancer therapy. This may be achieved by further structure-based drug design once the binding site on the p53 core domain is characterized. Small molecules have also been discovered that relieve the inhibition of p53 by MDM2 and E6 in cancers that express wild-type p53.

Abstract

One protein — p53 — plays nemesis to most cancers by condemning damaged cells to death or quarantining them for repair. But the activity of p53 relies on its intact native conformation, which can be lost following mutation of a single nucleotide. With thousands of such mutations identified in patients, how can a future cancer drug buttress this fragile protein structure and restore the cell's natural defence?

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Figure 1: p53 tumour suppression.
Figure 2: Structure of four p53 domains.
Figure 3: Frequency and distribution of p53 mutations.
Figure 4: Mutant classes mapped onto the core domain structure.
Figure 5: Mechanisms for drug rescue.
Figure 6: Small molecules stabilize the native p53 structure.

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Author information

Authors and Affiliations

  1. Department of Biochemistry, Box 357350, University of Washington, Seattle, 98195, USA

    Alex N. Bullock

  2. Cambridge University Chemical Laboratory and MRC Centre for Protein Engineering, Lensfield Road, Cambridge, CB2 1EW, UK

    Alan R. Fersht

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  1. Alex N. Bullock
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Correspondence to Alan R. Fersht.

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DATABASES

CancerNet

chronic myelogenous leukaemia

 GenBank

E6

 LocusLink

ABL

BCR

HSP90

MDM2

PML3

TP53

 Medscape DrugInfo

Gleevec

taxol

 OMIM

Li–Fraumeni syndrome

 Protein Data Bank

core domain

DNA-binding domain

regulatory domain

tetramerization domain

FURTHER INFORMATION

The IARC TP53 Mutation Database

Thierry Soussi's lab

LINKS

crystal structure

Glossary

LARGE T ANTIGEN

Tumour-associated protein encoded by the DNA-transforming virus SV40. It binds RB and p53 to overcome inhibition of cell growth.

DNA-DAMAGE CHECKPOINTS

The cell cycle can be arrested before the G1–S or G2–M phase transitions at checkpoints where DNA damage is detected.

β-SANDWICH

Tertiary protein structure common to all immunoglobulins. Consists of β-strands arranged into two β-sheets that pack together as a sandwich.

ENTHALPY OF DENATURATION

In order for a protein to be denatured as the temperature increases above the physiological level, many favourable stabilizing interactions within the protein have to be broken. The breaking of these requires input of energy from the surroundings — the 'enthalpy of denaturation'. The larger the enthalpy, the sharper the thermal transition.

HETERONUCLEAR SINGLE QUANTUM CORRELATION

(HSQC). Magnetization is transferred between the nuclei of 1H and 15N atoms in amide groups. A plot of the 15N against 1H chemical shifts produces a single crosspeak for each amino acid.

TWO-DIMENSIONAL NMR

NMR (nuclear magnetic resonance) spectroscopy measures the resonant absorption of radiofrequency radiation by magnetic nuclei in a magnetic field ('chemical shifts' that vary with environment; for example, with folding). Two-dimensional experiments use two magnetic nuclei, typically 1H and either 13C or 15N.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

E2F-1

A heterodimeric transcription factor that promotes cell cycle progression from G1 to S phase after phosphorylation and dissociation of RB. In tumours, deregulated E2F-1 promotes p53- and p73-dependent apoptosis.

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Bullock, A., Fersht, A. Rescuing the function of mutant p53. Nat Rev Cancer 1, 68–76 (2001). https://doi.org/10.1038/35094077

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