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1.
EMBO J ; 38(20): e102096, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31483066

RESUMEN

Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53-/- mice. Surprisingly, stabilization of p53R178E in Mdm2-/- mice nevertheless triggers extensive apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E ;Mdm2-/- embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53-/- mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53-/- ones, resulting in enhanced eradication of p53-mutated tumor cells. Together, this provides genetic proof-of-principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Leucemia Mieloide Aguda/prevención & control , Linfoma/prevención & control , Mutación , Proteínas Proto-Oncogénicas c-mdm2/fisiología , Proteína p53 Supresora de Tumor/fisiología , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Ciclo Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Linfoma/genética , Linfoma/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Tumorales Cultivadas
2.
Plant J ; 75(3): 469-83, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23607329

RESUMEN

Stem cells in the root and shoot apical meristem provide the descendant cells required for growth and development throughout the lifecycle of a plant. We found that mutations in the Arabidopsis MAINTENANCE OF MERISTEMS (MAIN) gene led to plants with distorted stem cell niches in which stem cells are not maintained and undergo premature differentiation or cell death. The malfunction of main meristems leads to short roots, mis-shaped leaves, reduced fertility and partial fasciation of stems. MAIN encodes a nuclear-localized protein and is a member of a so far uncharacterized plant-specific gene family. As main mutant plants are hypersensitive to DNA-damaging agents, expression of genes involved in DNA repair is induced and dead cells with damaged DNA accumulate in the mutant meristems, we propose that MAIN is required for meristem maintenance by sustaining genome integrity in stem cells and their descendants cells.


Asunto(s)
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Inestabilidad Genómica , Meristema/genética , Mutación , Proteínas Nucleares/genética , Proteínas de Arabidopsis/metabolismo , Diferenciación Celular/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Daño del ADN/genética , Regulación de la Expresión Génica de las Plantas , Proteínas Nucleares/metabolismo , Fenotipo , Raíces de Plantas/genética , Brotes de la Planta/genética , Semillas/genética , Semillas/crecimiento & desarrollo
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