Mutant p53: One name, many proteins

Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Genes & development (Impact Factor: 10.8). 06/2012; 26(12):1268-86. DOI: 10.1101/gad.190678.112
Source: PubMed

ABSTRACT There is now strong evidence that mutation not only abrogates p53 tumor-suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function.

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    • "In Li-Fraumeni patients, missense mutation was reported to lead to earlier tumor onset than other forms of p53 loss (Bougeard et al. 2008). p53 hot spot mutant proteins have been reported to associate with chromatin and alter a cell's transcriptional profile, leading to oncogenic cellular changes (Di Agostino et al. 2006; Stambolsky et al. 2010; Do et al. 2012; Freed-Pastor et al. 2012; Cooks et al. 2013). Although a common view is that p53 hot spot mutants acquire neomorphic properties , many activities of mutant p53 are likely conserved from wild-type p53 and generate different cellular outcomes due to differences in their distribution within cellular chromatin. "
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    ABSTRACT: Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential. © 2015 Pfister et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 06/2015; 29(12). DOI:10.1101/gad.263202.115 · 10.80 Impact Factor
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    • "Furthermore, the molecular network(s) specifically activated in p53-deficient contexts may promote proliferation of cancer cells. Several lines of evidence strongly suggest that TP53 mutations contribute to maintenance of the malignant gain-of-function phenotypes of cancer cells, including cell-cycle progression and activation of cell migration, as well as loss of wild-type tumor-suppressor functions6. In light of this novel concept, mutant p53 is an attractive target for therapeutics directed against a wide range of cancers. "
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    ABSTRACT: Dysfunction of the p53 network is a major cause of cancer development, and selective elimination of p53-inactivated cancer cells therefore represents an ideal therapeutic strategy. In this study, we performed a microRNA target screen that identified NEK9 (NIMA-related kinase 9) as a crucial regulator of cell-cycle progression in p53-inactivated cancer cells. NEK9 depletion selectively inhibited proliferation in p53-deficient cancer cells both in vitro and in vivo. The resultant cell-cycle arrest occurred predominantly in G1 phase, and exhibited senescence-like features. Furthermore, NEK9 repression affected expression of a broad range of genes encoding cell-cycle regulators and factors involved in mRNA processing, suggesting a novel role for NEK9 in p53-deficient cells. Lung adenocarcinoma patients with positive staining for NEK9 and mutant p53 proteins exhibited significantly poorer prognoses, suggesting that expression of both proteins promotes tumor growth. Our findings demonstrate that a novel NEK9 network regulates the growth of cancer cells lacking functional p53.
    Scientific Reports 08/2014; 4:6111. DOI:10.1038/srep06111 · 5.58 Impact Factor
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    • "The most frequent mutations in p53 result in the change/loss of wild-type transcriptional activity. Interestingly mutant p53 retains transcriptional function through both direct and indirect mechanisms [28]. Nonetheless, reactivation of wild-type p53 transcriptional activity has been sought as a good indicator of the success of a chemical screen. "
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    ABSTRACT: Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful.
    Apoptosis 04/2014; 19(7). DOI:10.1007/s10495-014-0990-3 · 3.69 Impact Factor
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