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


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
    • "An intriguing new strategy to improve anticancer therapy is drugging the p53 pathway [4]. It is well established that p53 is the most commonly mutated protein in human malignancies, about half of them harbour mutant p53 (mt-p53) genes [5]. But also the 50% of cancers in which p53's function is not compromised by mutation frequently have disabled p53 pathways, e.g. as a result of increased levels of the p53 inhibitory proteins MDM2 or MDM4 (also known as MDMX) [4]. "
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    ABSTRACT: Mutant p53 can exert oncogenic activity by inhibitory interaction with p73. The small-molecule RETRA has been described to disrupt this interaction and to suppress carcinoma cells (Kravchenko et al., 2008). RETRA's anticancer activity was restricted to tumour cells bearing mutant p53; it was not active in p53 negative and in p53 wild-type cells. Here, we explored the responsiveness of Ewing's sarcoma (ES) cells with mutant p53 to RETRA. For comparison, we also tested RETRA in p53 null and in p53 wild-type ES cells. We found RETRA to be effective in the three mutant p53 ES cell lines investigated. Strikingly, however, RETRA was similarly effective in the p53-deficient and in the two p53 wild-type ES cell lines examined. RETRA elicited apoptosis, as assessed by flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation, caspase 3/7 activity assay and PARP-1 cleavage immunodetection, and G2/M cell cycle arrest completely independent of the cellular TP53 status. In contrast, various p53-deficient and -proficient carcinoma, osteosarcoma and leukaemia cells were unresponsive to RETRA. RETRA also induced gene expression of p53 target genes PUMA and p21 in ES cells irrespective of their TP53 status. These in vitro findings provide a rationale for an in vivo exploration of RETRA's potential as an effective therapeutic approach for patients with ES. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 03/2015; 51(7). DOI:10.1016/j.ejca.2015.02.016 · 5.42 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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