Crippling p53 activities via knock-in mutations in mouse models

Iwakuma, Tomoo; Lozano, Guillermina

doi:10.1038/sj.onc.1210278

Cited by 60 publications

(47 citation statements)

References 77 publications

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“…This is unlike the S23A and S389A mice which develop tumors much later in life, probably on accumulation of genetic anomalies over time. 1,33 Nevertheless, no defects on ER stress were also observed in these mutant cells, raising the possibility that this site is indeed dispensable for all tested p53 functions. However, we cannot exclude the possibility that a phenotype may be apparent in sensitized backgrounds.…”

Section: Discussionmentioning

confidence: 94%

“…Although single phospho-mutant p53 knock-in mice behaved very similar to the WT mice, the S18/23A mutant, in which both S18 and S23 residues are unphosphorylatable, is almost completely defective in apoptosis and developed an array of spontaneous tumors, 1,[33][34][35][36] showing that mutating multiple phosphorylation sites have synergistic effects on p53 functions. Therefore, it is possible that mice in which multiple phosphorylation sites such as S18/23/312A are altered may reveal the functional significance of S312, and requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Serine 312 phosphorylation is dispensable for wild-type p53 functions in vivo

et al. 2010

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Cellular stimulation results in phosphorylation of the tumor suppressor p53 on multiple residues, though the functional relevance is not always clear. It is noteworthy that the serine (S) 315 residue is unique, as it has been suggested to be phosphorylated not only by genotoxic signals, but also during cell-cycle progression and by endoplasmic-reticulum stress. However, in vitro data have been conflicting as phosphorylation at this site was shown to both positively and negatively regulate p53 functions. We have thus generated knock-in mice expressing an unphosphorylable S312 (equivalent to human S315), by substitution with an alanine (A) residue, to clarify the conflicting observations and to evaluate its functional relevance in vivo. Born at Mendelian ratios, the p53 S312A/S312A mice show no anomalies during development and adulthood. p53 activation, stability, localization and ability to induce apoptosis, cell-cycle arrest and prevent centrosome amplification are not compromised in p53 S312A/S312A cells. p53 S312A/S312A mice are unable to rescue mdm2 À/À lethality, and tumorigenesis -both spontaneous and irradiation/oncogene-induced -is not accentuated. Taken together, the results show that the S312 phosphorylation site is not in itself necessary for efficient p53 function, and advocates the possibility that it is neither relevant in the mouse context nor important for p53 functions in vivo.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Serine 312 phosphorylation is dispensable for wild-type p53 functions in vivo

et al. 2010

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“…Several isoforms of p53 have been identified (Courtois et al, 2002;Candeias et al, 2006;Grover et al, 2009;Marcel and Hainaut, 2009), and point mutations influencing the functionality of p53 were elucidated and mimicked in vivo (de Vries et al, 2002;Wijnhoven et al, 2005;Hoogervorst et al, 2005a;Iwakuma and Lozano, 2007;Heinlein et al, 2008). The p53 gene is the most frequently mutated gene in cancer and analysis of many different human tumor types have shown a high prevalence of missense mutations located primarily in the central DNA-binding domain (Levine, 1997).…”

Section: Introductionmentioning

confidence: 99%

Genotoxic exposure: novel cause of selection for a functional ΔN-p53 isoform

Melis¹,

Hoogervorst²,

Oostrom³

et al. 2010

Oncogene

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The p53 gene is frequently mutated in cancers and it is vital for cell cycle control, homeostasis and carcinogenesis. We describe a novel p53 mutational spectrum, different to those generally observed in human and murine tumors. Our study shows a high prevalence of nonsense mutations in the p53 N terminus of 2-acetylaminofluorene (2-AAF)-induced urinary bladder tumors. These nonsense mutations forced downstream translation initiation at codon 41 of Trp53, resulting in the aberrant expression of the p53 isoform DN-p53 (or p44). We propose a novel mechanism for the origination and the selection for this isoform. We show that chemical exposure can act as a novel cause of selection for this truncated protein. In addition, our data suggest that the occurrence of DN-p53 accounts, at least in mice, for a cancer phenotype. We also show that gene expression profiles of embryonic stem (ES) cells carrying the DN-p53 isoform in a p53-null background are divergent from p53 knockout ES cells, and therefore postulate that DN-p53 itself has functional transcriptional properties.

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“…Several post-translational modifications of p53 (reviewed in [48]) can be abolished without any significant phenotype [49], suggesting that functional redundancy evolved to ensure p53 regulation maintenance and each specific combination of different modifications trigger the exact p53 functions including specific localization, degradation rate and transcriptional activity. To unravel this complex scenario, it is useful to evaluate the conservation of these amino acid residues and reconstruct the evolution of the p53 locus.…”

Section: P53 Conservation Between Fish and Mammalsmentioning

confidence: 99%

Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri

Priami¹,

Michele²,

Cotelli³

et al. 2015

Aging and disease

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Oxidative stress induced by reactive oxygen species (ROS) increases during lifespan and is involved in aging processes. The p66Shc adaptor protein is a master regulator of oxidative stress response in mammals. Ablation of p66Shc enhances oxidative stress resistance both in vitro and in vivo. Most importantly, it has been demonstrated that its deletion retards aging in mice. Recently, new insights in the molecular mechanisms involving p66Shc and the p53 tumor suppressor genes were given: a specific p66Shc/p53 transcriptional regulation pathway was uncovered as determinant in oxidative stress response and, likely, in aging. p53, in a p66Shc-dependent manner, negatively downregulates the expression of 200 genes which are involved in the G2/M transition of mitotic cell cycle and are downregulated during physiological aging. p66Shc modulates the response of p53 by activating a p53 isoform (p44/p53, also named Delta40p53). Based on these latest results, several developments are expected in the future, as the generation of animal models to study aging and the evaluation of the use of the p53/p66Shc target genes as biomarkers in aging related diseases. The aim of this review is to investigate the conservation of the p66Shc and p53 role in oxidative stress between fish and mammals. We propose to approach this study trough a new model organism, the annual fish Nothobranchius furzeri, that has been demonstrated to develop typical signs of aging, like in mammals, including senescence, neurodegeneration, metabolic disorders and cancer.

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Crippling p53 activities via knock-in mutations in mouse models

Cited by 60 publications

References 77 publications

Serine 312 phosphorylation is dispensable for wild-type p53 functions in vivo

Serine 312 phosphorylation is dispensable for wild-type p53 functions in vivo

Genotoxic exposure: novel cause of selection for a functional ΔN-p53 isoform

Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri

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