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      Regulators of Oncogenic Mutant TP53 Gain of Function

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          Abstract

          The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin ligases, and molecular chaperones, as well as a single nucleotide polymorphism (SNP) and dimer-forming mutations in mutp53.

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          Mutant p53 in Cancer: New Functions and Therapeutic Opportunities

          Patricia A.J. Muller, Karen H. Vousden (2014)
          Many different types of cancer show a high incidence of TP53 mutations, leading to the expression of mutant p53 proteins. There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression. Understanding the functions of mutant p53 will help in the development of new therapeutic approaches that may be useful in a broad range of cancer types.
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            Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome.

            Kenneth P Olive, David Tuveson, Zachary Ruhe … (2004)
            The p53 tumor suppressor gene is commonly altered in human tumors, predominantly through missense mutations that result in accumulation of mutant p53 protein. These mutations may confer dominant-negative or gain-of-function properties to p53. To ascertain the physiological effects of p53 point mutation, the structural mutant p53R172H and the contact mutant p53R270H (codons 175 and 273 in humans) were engineered into the endogenous p53 locus in mice. p53R270H/+ and p53R172H/+ mice are models of Li-Fraumeni Syndrome; they developed allele-specific tumor spectra distinct from p53+/- mice. In addition, p53R270H/- and p53R172H/- mice developed novel tumors compared to p53-/- mice, including a variety of carcinomas and more frequent endothelial tumors. Dominant effects that varied by allele and function were observed in primary cells derived from p53R270H/+ and p53R172H/+ mice. These results demonstrate that point mutant p53 alleles expressed under physiological control have enhanced oncogenic potential beyond the simple loss of p53 function.
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              Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome.

              Gene Lang, Tomoo Iwakuma, Young-Ah Suh … (2004)
              Individuals with Li-Fraumeni syndrome carry inherited mutations in the p53 tumor suppressor gene and are predisposed to tumor development. To examine the mechanistic nature of these p53 missense mutations, we generated mice harboring a G-to-A substitution at nucleotide 515 of p53 (p53+/515A) corresponding to the p53R175H hot spot mutation in human cancers. Although p53+/515A mice display a similar tumor spectrum and survival curve as p53+/- mice, tumors from p53+/515A mice metastasized with high frequency. Correspondingly, the embryonic fibroblasts from the p53515A/515A mutant mice displayed enhanced cell proliferation, DNA synthesis, and transformation potential. The disruption of p63 and p73 in p53-/- cells increased transformation capacity and reinitiated DNA synthesis to levels observed in p53515A/515A cells. Additionally, p63 and p73 were functionally inactivated in p53515A cells. These results provide in vivo validation for the gain-of-function properties of certain p53 missense mutations and suggest a mechanistic basis for these phenotypes.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 20 December 2018
                Publication date Collection: January 2019
                Volume: 11
                Issue: 1
                Electronic Location Identifier: 4
                Affiliations
                [1 ]Department of Cancer Biology, The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66010, USA; syamamoto@ 123456kumc.edu
                [2 ]Department of Hematology and Oncology, Children’s Mercy Research Institute, Kansas City, MO 64108, USA
                Author notes
                [* ]Correspondence: tiwakuma@ 123456kumc.edu or tiwakuma@ 123456cmh.edu ; Tel.: +1-913-588-7412
                Article
                Publisher ID: cancers-11-00004
                DOI: 10.3390/cancers11010004
                PMC ID: 6356290
                PubMed ID: 30577483
                SO-VID: d3f86cba-851e-414a-8e29-db9c3b9f8355
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 15 November 2018
                Date accepted : 18 December 2018
                Categories
                Subject: Review

                Keywords: tp53,mutant tp53,gain of function,post-translational modification,molecular chaperone,single nucleotide polymorphism,dimer-forming mutation
                Data availability:
                Keywords: tp53, mutant tp53, gain of function, post-translational modification, molecular chaperone, single nucleotide polymorphism, dimer-forming mutation

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