Gain‐of‐Function Mutants of p53 and Their Role in Tumourigenesis

Abstract

The p53 gene is a tumour suppressor that is widely mutated in human cancers. Wild‐type p53 plays a pivotal role in preventing deoxyribonucleic acid (DNA) damage and maintaining the integrity of the cell. Cells that contain mutant p53, however, are unable to prevent this damage and, in fact, become more oncogenic. Gain‐of‐function (GOF) mutant p53 has been shown to transactivate a number of genes that are part of cell growth and survival pathways and cause an increase in tumourigenicity. Knockin and transgenic mouse models have been utilised to explore the GOF phenotype of mutant p53. Currently, p53 cannot be targeted for cancer therapy, but recent studies have demonstrated the ability to reduce tumourigenicity in lung cancer cells addicted to their endogenous GOF mutant p53.

Key Concepts:

  • The p53 gene is the most frequently mutated tumour suppressor gene in cancer.

  • WT p53 plays an active role in the cell cycle, DNA repair, apoptosis, and can function as a transcriptional activator.

  • A wide array of functions of WT p53 are dependent on its transcriptional ability.

  • Gain‐of‐function mutations are characterised by loss of the wild‐type tumour suppressor functions of p53 as well as gain of new oncogenic functions.

  • Several groups have utilized mouse models to study mutant p53 gain of function in cancer.

Keywords: mutant; p53; transactivation; oncogenesis; gain of function

Figure 1.

Schematic of p53 protein indicating several mutations within the DNA‐binding domain.

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Vaughan, Catherine A, Deb, Swati P, and Deb, Sumitra(Feb 2014) Gain‐of‐Function Mutants of p53 and Their Role in Tumourigenesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022449]