Abstract
The p53 family of proteins has grown substantially over the last 40 years. It started with p53, then p63, p73, isoforms and mutants of these proteins. The function of p53 as a tumour suppressor has been thoroughly investigated, but the functions of all isoforms and mutants and the interplay between them are still poorly understood. Mutant p53 proteins lose p53 function, display dominant-negative (DN) activity and display gain-of-function (GOF) to varying degrees. GOF was originally attributed to mutant p53′s inhibitory function over the p53 family members p63 and p73. It has become apparent that this is not the only way in which mutant p53 operates as a large number of transcription factors that are not related to p53 are activated on mutant p53 binding. This raises the question to what extent mutant p53 binding to p63 and p73 plays a role in mutant p53 GOF. In this review, we discuss the literature around the interaction between mutant p53 and family members, including other binding partners, the functional consequences and potential therapeutics.
Highlights
In 1979 the research into p53 started off with the finding of a 53kDa protein using immunoprecipitation with the SV40 T antigen in transformed cells [1,2,3]
The mutant proteins are almost always caused by single nucleotide changes in the DNA, resulting in mutant proteins that differ in only one amino acid from the wildtype molecule
Increased stability of the mutant might be a prerequisite for gain-of-function as normal levels of mutant p53 are observed in most tissues of Li-Fraumeni patients and mutant p53 mouse models, whereas most tumours overexpress mutant p53 [20,21]
Summary
In 1979 the research into p53 started off with the finding of a 53kDa protein using immunoprecipitation with the SV40 T antigen in transformed cells [1,2,3]. Increased stability of the mutant might be a prerequisite for gain-of-function as normal levels of mutant p53 are observed in most tissues of Li-Fraumeni patients and mutant p53 mouse models, whereas most tumours overexpress mutant p53 [20,21]. This is substantiated by the finding that stresses that stabilise the wildtype p53 protein promote mutant p53 stabilisation and potentiate tumourigenesis in mouse models [22]. We will focus on how mutant p53 inhibits p63 and p73 and to what extent this inhibition contributes to mutant p53 gain-of-function in vivo
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