Abstract
TP53 is one of the most frequently inactivated tumor suppressor genes in human cancer. However, unlike other tumor suppressor genes whose expression is lost, TP53 is usually inactivated as a result of a single nucleotide change within the coding region. Typically, these single nucleotide mutations result in a codon change that creates an amino acid substitution. Thus, unlike other tumor suppressor genes whose expression is lost due to genetic or epigenetic changes, the p53 gene primarily suffers missense mutations, and therefore, the cells retain and express a mutant form of the p53 protein (mtp53). It is now well established that mtp53 contributes to tumor development through its gain-of-function (GOF) activities. These GOF activities can arise from novel protein–protein interactions that can either disable other tumor suppressors (e.g., p63 and p73) or enable oncogenes such as ETS2, an ETS family member. In this review, I will focus on the identification of the mtp53/ETS2 complex and outline the diverse activities that this transcriptional regulatory complex controls to promote cancer.
Highlights
Reviewed by: Takaomi Sanda, National University of Singapore, Singapore Giovanni Sorrentino, Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, Italy
The majority of mutations in the p53 gene cluster within the region that encodes the DNA-binding domain. Some of these mutations alter the overall conformation of the protein, while other mutations do not alter the structure but instead change an amino acid that is critical for DNA binding [1, 2]. These mutations typically give rise to mtp53 proteins that have lost the capacity to bind to the wild-type p53 (WTp53) consensus binding site and are unable to associate with WTp53 response elements in the genome and unable to regulate WTp53 target genes
It was shown that mtp53 functions in a manner that is diametrically opposed to the tumor suppressor functions of WTp53
Summary
Reviewed by: Takaomi Sanda, National University of Singapore, Singapore Giovanni Sorrentino, Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, Italy. Many of these transcription factors that bind to mtp53 have been shown to interact with WTp53 (E2F1, NF-Y, VDR, ETS1, ETS2, and SP1), there are some discrepancies among different studies [7,8,9,10,11,12]. It is possible that there might be tissue-specific or stress-dependent conditions that permit WTp53 to interact with ETS family members, some studies were conducted in vitro.
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