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  • Review Article
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When mutants gain new powers: news from the mutant p53 field

Nature Reviews Cancer volume 9, pages 701–713 (2009)Cite this article

Key Points

  • The tumour suppressor p53 (encoded by TP53 in humans) functions primarily as a transcription factor, which, upon cellular stress signals, regulates a plethora of genes that promote cell cycle arrest, senescence, apoptosis, differentiation, DNA repair and other processes.

  • TP53 is somatically mutated in the majority of sporadic human cancers, and mutations in TP53 are also associated with Li–Fraumeni Syndrome, a familial cancer predisposition syndrome.

  • The majority of cancer-associated mutations in TP53 are missense mutations in its DNA-binding domain. These mutations usually lead to the formation of a full-length mutant protein (mutant p53) incapable of activating p53 target genes and suppressing tumorigenesis. Besides losing their wild-type activities, many p53 mutants also function as dominant-negative proteins that inactivate wild-type p53 expressed from the remaining wild-type allele. Moreover, some mutant p53 forms also acquire new oncogenic properties that are independent of wild-type p53, known as 'gain-of-function' properties.

  • In the past three decades ample data were collected in support of the importance of mutant p53 gain-of-function properties for tumorigenesis. These data include cell culture studies that demonstrated the capability of mutant p53 to impinge on pivotal cellular regulatory networks, mouse models that established the ability of mutant p53 to increase tumour aggressiveness and metastatic potential, as well as clinical studies that revealed associations between TP53 mutations and poor clinical outcome in a variety of malignancies.

  • This Review describes recent advances in the research field of mutant p53, with an emphasis on the transcriptional effects of mutant p53, the expression signatures associated with TP53 mutations in vitro and in vivo and the diagnostic, prognostic and predictive value of TP53 mutations in human cancer.

Abstract

Ample data indicate that mutant p53 proteins not only lose their tumour suppressive functions, but also gain new abilities that promote tumorigenesis. Moreover, recent studies have modified our view of mutant p53 proteins, portraying them not as inert mutants, but rather as regulated proteins that influence the cancer cell transcriptome and phenotype. This influence is clinically manifested as association of TP53 mutations with poor prognosis and drug resistance in a growing array of malignancies. Here, we review recent studies on mutant p53 regulation, gain-of-function mechanisms, transcriptional effects and prognostic association, with a focus on the clinical implications of these findings.

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Figure 1: Selected oncogenic properties of mutant p53 and their underlying mechanisms.
Figure 2: Distribution of TP53 somatic mutations according to the IARC TP53 Mutation Database.
Figure 3: Association of TP53 mutations and clinical outcome in selected cancer types.

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Acknowledgements

Supported by a Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI). V.R. is the incumbent of the Norman and Helen Asher Professorial Chair for Cancer Research at the Weizmann institute.

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  1. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Ran Brosh & Varda Rotter

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  1. Ran Brosh
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DATABASES

National Cancer Institute Drug Dictionary 

doxorubicin

vitamin D

OMIM

Li–Fraumeni Syndrome

FURTHER INFORMATION

IARC TP53 Mutation Database

Glossary

Loss of heterozygosity

(LOH). A genetic event at a particular locus heterozygous for a mutant allele and a wild-type allele in which the wild-type allele is either deleted (rendering the cell hemizygous for the mutated allele) or mutated (rendering the cell homozygous for the mutant allele).

Missense mutation

A single base-pair substitution that results in the translation of a different amino acid at that position.

Transition

A mutation that results in a substitution of a purine for a purine or a pyrimidine for a pyrimidine.

Transversion

A mutation that results in a substitution of a purine for a pyrimidine or vice versa.

Aflatoxin B1

A potent mutagenic fungal-produced toxin. Human exposure to aflatoxin B1 largely stems from Aspergillus spp. food contamination, which occurs primarily in eastern Asia and sub-Saharan Africa. Aflatoxin B1 promotes GT transversions and is associated with a substitution of an arginine (AGG) to a serine (AGT) at TP53 codon R249, the most common TP53 mutation in hepatocellular carcinoma.

Focus formation assay

An in vitro assay used to measure the oncogenic potential of a gene. Usually, the gene of interest is delivered into animal cells which normally show contact inhibition. A bona fide oncogene grants the cells the ability to form areas of multi-layered densely-packed cells (called foci).

Penetrance

A measure of the proportion of individuals carrying a gene variation (for example, a mutation or single nucleotide polymorphism) that also express a phenotypical trait associated with that genetic variation (for example, a disease).

Autophagy

A cellular catabolic degradation response to stress involving engulfing, degradation and recycling of intracellular material.

Single nucleotide polymorphism

(SNP). A germline variation in a single nucleotide that exists at a frequency of at least 1% in the general population.

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Brosh, R., Rotter, V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9, 701–713 (2009). https://doi.org/10.1038/nrc2693

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