Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

Abstract

Although still controversial, the presence of mutant p53 in cancer cells may result in more aggressive tumors and correspondingly worse outcomes. The means by which mutant p53 exerts such pro-oncogenic activity are currently under extensive investigation and different models have been proposed. We focus here on a proposed mechanism by which a subset of tumor-derived p53 mutants physically interact with p53 family members, p63 and p73, and negatively regulate their proapoptotic function. Both cell-based assays and knock-in mice expressing mutant forms of p53 support this model. As more than half of human tumors harbor mutant forms of p53 protein, approaches aimed at disrupting the pathological interactions among p53 family members might be of clinical value.

Helicobacter pylori Infection and a P53 Codon 72 Single Nucleotide Polymorphism: a Reason for an Unexplained Asian Enigma

“…Of these, the codon 72 polymorphism (rs1042522) is by far the more common, which results in the substitution of arginine (Arg) by proline (Pro) in the transactivating domain.54Changes in its amino acid sequence can alter the ability of p53 to bind to receptors in target genes, alter DOI:http://dx.doi.org/10.7314/APJCP.2014.15.21.9171 Helicobacter pylori Infection and a P53 Codon 72 SNP: a Reason for an Unexplained Asian Enigma recognition motifs for post-translational modifications or alter p53 stability and interactions with other proteins (Walker and Levine, 1996;Thomas, 1999;Shepherd et al, 2002;Bergamaschi et al, 2003;Li and Prives, 2007). Such changes may contribute to tumor progression and a poor prognosis (Katkoori et al, 2009).…”

The disruption of the protein complex mutantp53/p73 increases selectively the response of tumor cells to anticancer drugs

“…5,6,10,26,27 There is no exhaustive knowledge allowing a functional classification of mutant p53 proteins that might predict the degree of gain of function activity and consequently its impact on clinical outcome. Furthermore, we provide evidence supporting that the molecular target of SIMPs activity is the disassembling of the protein complex mutantp53/p73.…”

“…Growing evidence is highlighting the core of mutantp53 as a critical modular domain through which mutantp53 takes part in multi-protein complexes including transcription factors, co-activators, acetylates, deacetylases and scaffold proteins. 6,9,10,27 There is yet scarce evidence to clearly define whether mutations in the core domain of mutant p53 dictate the binding to specific interactors that are not shared either by wt-p53 or by other human tumor derived p53 mutants. Mutantp53/p73 protein complexes are readily detectable in tumor cells, while those Dot immunobinding assay.…”

“…11,13,21 This might suggest that the core of mutant p53 plays a critical role in the selective formation of the complex with p73, thereby conferring to mutant p53 proteins additional gain of function properties. 6,15,27 This might account for the strong selection pressure for p53 mutations within the core domain of the protein.…”

A New Isoquinolinium Derivative, Cadein1, Preferentially Induces Apoptosis in p53-defective Cancer Cells with Functional Mismatch Repair via a p38-dependent Pathway

“…p53 ϩ/ϩ mouse embryonic fibroblasts transformed by adenoviral E1A protein and Ha-ras oncogene undergo apoptosis in response to ␥-irradiation or chemotherapeutic agents, whereas p53 Ϫ/Ϫ fibroblasts are resistant to these anti-cancer therapies (5). In addition, some p53 mutations in cancers suppress the function of p73, which induces apoptosis through a p53-independent mechanism (6). Thus, the common loss of p53 function in cancer cells presents a major limitation for anti-cancer therapies.…”