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Un modelo para la apoptosis inducida por p53
1The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nature
|September 26, 1997
Resumen
La proteína supresora de tumores p53 desencadena la apoptosis a través de un nuevo proceso de tres pasos que involucra el estrés oxidativo. Este descubrimiento arroja luz sobre p53.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Investigación de Investigación del Cáncer.
- Mecanismos de muerte celular Mecanismos de muerte celular
Sus antecedentes:
- El gen supresor de tumores p53 se inactiva con frecuencia en los cánceres humanos, lo que lleva a investigar sus funciones.
- La expresión de p53 puede inducir la detención del ciclo celular o la apoptosis, pero los mecanismos de la apoptosis dependiente de p53 no se comprenden completamente.
- Si bien la detención del crecimiento inducida por p53 en el cáncer colorrectal involucra p21WAF1 / CIP1, la vía apoptótica sigue sin caracterizarse en gran medida.
Objetivo del estudio:
- Para investigar los objetivos transcripcionales de p53 que preceden a la apoptosis.
- Para dilucidar los mecanismos moleculares subyacentes a la muerte celular programada mediada por p53.
Principales métodos:
- El perfil de expresión génica se utilizó para identificar transcripciones reguladas al alza por la expresión de p53.
- Análisis de 7.202 transcripciones en células que expresan p53 frente a células de control.
- Se realizaron experimentos bioquímicos y farmacológicos para validar los hallazgos.
Principales resultados:
- Sólo 14 (0.19%) de 7.202 transcripciones se incrementaron significativamente en la expresión de p53.
- Se predijo que muchos genes upregulated estarían involucrados en respuestas al estrés oxidativo.
- Se propuso una nueva vía apoptótica de tres pasos inducida por p53: inducción de genes redox, generación de especies reactivas de oxígeno y daño mitocondrial.
Conclusiones:
- La apoptosis inducida por p53 está mediada por la regulación al alza transcripcional de genes relacionados con la redox.
- La formación de especies reactivas de oxígeno y la posterior degradación oxidativa de las mitocondrias son eventos clave en la muerte celular dependiente de p53.
- Este estudio revela un nuevo mecanismo para la apoptosis impulsada por p53 que involucra estrés oxidativo.
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