When mutants gain new powers: news from the mutant p53 field

Brosh, Ran; Rotter, Varda

doi:10.1038/nrc2693

Cited by 1,017 publications

(1,107 citation statements)

References 177 publications

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“…Mutant p53 and miR-155 expression are both associated with invasive properties in vivo (2,10), which prompted us to investigate whether they promote malignant transformation through a similar oncogenic axis. We initially determined if miR-155 can phenocopy mutant p53 in its ability to drive invasion and mensenchymal transformation when expressed in the same genetic background.…”

Section: Mir-155 Is a Target Microrna Of Mutant P53mentioning

confidence: 99%

“…However, inactivation of the tumor suppressor function of p53 is not the only outcome of a TP53 mutation. Increasing evidence suggests that the mutated p53 protein exhibits traits consistent with the acquisition of an oncogenic gain-of-function (1,2). For example, mutations of TP53 gene are frequently missense, involve similar codons within the p53 DNA binding domain and are expressed at remarkably high levels in tumor cells (1).…”

Section: Introductionmentioning

confidence: 99%

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Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

et al. 2012

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Section: Mir-155 Is a Target Microrna Of Mutant P53mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

et al. 2012

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“…Two apparently contradictory results blur our vision as to the role of p53 in skin cancer: mice deficient for TP53 develop tumors resembling SCC after UV irradiation (Ziegler et al, 1994;Li et al, 1998;Jiang et al, 1999), whereas Li-Fraumeni syndrome patients, who have a germline mutation in TP53, are not reported to be at increased risk for SCC (Malkin et al, 1990). These findings should be put in the perspective of the growing body of evidence showing that p53 missense mutants not only lose normal p53 functions, but are also often pro-active in tumor formation (reviewed by Donzelli et al, 2008;Brosh and Rotter, 2009). Indeed, a set of gain-of-function mechanisms resulting from p53 mutations have been documented.…”

Section: Activation Of Klf4 By Mutant P53mentioning

confidence: 99%

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

et al. 2010

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Genetic experiments established that p63 is crucial for the development and maintenance of pluri-stratified epithelia and KLF4 for the barrier function of the skin. KLF4 is one of the factors that reprogram differentiated cells to iPS. We investigated the relationship between p63 and KLF4 using RNA interference, overexpression, chromatin immunoprecipitation and transient transfections with reporter constructs. We find that p63 directly represses KLF4 in normal keratinocytes (KCs) by binding to upstream promoter sites. Unlike p63, KLF4 levels are high in the upper layers of human skin and increase upon differentiation of KCs in vitro. In HaCaT KCs, which harbor two mutant alleles of p53, inactivation of p63 and of mutant p53 leads to KLF4 repression. p63 and p53 mutants are bound to sites in the KLF4 core promoter. Importantly, expression of the H179Y and R282Q p53 mutants in primary KCs is sufficient to activate endogenous KLF4. Finally, immunohistochemical analysis of tissue arrays confirms increased coexpression of KLF4 and mutant p53 in squamous cell carcinomas. Our data indicate that suppression of KLF4 is part of the growth-promoting strategy of p63 in the lower layers of normal epidermis, and that tumor-predisposing p53 mutations hijack p63 to a different location on the promoter, turning it into an activator of this reprogramming factor.

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“…RD cells carry a homozygous p53 Arg248Trp mutation, 29,30 which renders the protein defective in DNA binding. 3 Wild-type p53 function was restored in RD cells by expressing a tamoxifen-inducible p53-estrogen receptor (ER) fusion (Figure 1a). By tuning the translation level 31 of the p53-ER ( Supplementary Figures 1 and 2a-c), we showed that restoration of wild-type p53 over a range of expression levels did not result in apoptotic and/or necrotic cells 32 in RD cells (Supplementary Figures 2d-g).…”

Section: Resultsmentioning

confidence: 99%

“…[1][2][3] Among the diverse functions attributed to p53, a growing body of evidence supports its role in regulation of differentiation and maintenance of cellular function and integrity. 1,[4][5][6][7] For example, p53 represses Nanog to maintain genetic stability of the stem cell pool by promoting differentiation of mouse embryonic stem cells (mESCs) after DNA damage.…”

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confidence: 99%

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

et al. 2014

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Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging. Cell Death and Differentiation (2015) 22, 560-573; doi:10.1038/cdd.2014; published online 12 December 2014The tumor suppressor p53 promotes cell cycle arrest or apoptosis in response to diverse stress signals such as DNA damage, thus preventing propagation of genetically compromised cells. [1][2][3] Among the diverse functions attributed to p53, a growing body of evidence supports its role in regulation of differentiation and maintenance of cellular function and integrity. 1,[4][5][6][7] For example, p53 represses Nanog to maintain genetic stability of the stem cell pool by promoting differentiation of mouse embryonic stem cells (mESCs) after DNA damage. 6 Skeletal muscle differentiation, a key step during muscle tissue formation, is orchestrated by the MyoD family of myogenic regulatory factors (MRFs). MyoD determines the myogenic lineage, whereas myogenin, a member of the MRF family, functions downstream of MyoD and plays a critical role in driving terminal differentiation as myogenin-null mice show a lethal deficiency of differentiated skeletal muscle. [8][9][10][11][12][13] The dynamic differentiation program of skeletal muscle is characterized by the orderly expression of genes and structural changes that can be recapitulated in vitro, as myogenic cells undergo cell cycle withdrawal and express early and then late differentiation genes with the formation of mononucleated myocytes to elongated multinucleated myotubes. 8,9,14 Under normal unstressed conditions, p53 has been shown to promote muscle differentiation in vitro. [15][16][17][18][19][20] In contrast, under stress-associated conditions such as inflammation, chronic exposure to double-strand DNA breaks, and aging, enhanced p53 activity has been shown to correlate with skeletal muscle atrophy in vivo. [21][22][23][24][25] In addition, it has been shown that p53 and its downstream effectors are required for an inflammatory cytokine-mediated inhibition of myogenic differentiation in vitro. 22 Int...

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When mutants gain new powers: news from the mutant p53 field

Cited by 1,017 publications

References 177 publications

Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress

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