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Los distintos programas de transcripción p53 dictan respuestas agudas de daño al ADN y supresión de tumores
Colleen A Brady1, Dadi Jiang, Stephano S Mello
1Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell
|May 14, 2011
Resumen
La proteína supresora de tumores p53 es esencial para la prevención del cáncer, pero sus mecanismos no están claros. Este estudio revela que el p53
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Investigación de Investigación del Cáncer.
- Genética La genética.
Sus antecedentes:
- No se comprenden completamente los mecanismos moleculares precisos que subyacen a la supresión tumoral mediada por p53.
- p53 es una proteína supresora de tumores crítica involucrada en las respuestas celulares al daño del ADN.
Objetivo del estudio:
- Para dilucidar los distintos programas de transcripción de p53 en la supresión de tumores y la respuesta al daño del ADN.
- Para investigar el papel de la transactivación de p53 en la senescencia y la supresión de tumores utilizando modelos de ratón knockin.
Principales métodos:
- Se utilizaron ratones knockin que expresaban una serie de mutantes de activación transcripcional de p53.
- Se realizó un análisis de microarrays para evaluar la transactivación génica.
- Actividad evaluada del mutante p53 en la detención de la G1, la apoptosis, la senescencia y la supresión tumoral.
Principales resultados:
- Un mutante de p53 (p53 25,26) mostró una transactivación comprometida de la mayoría de los genes diana y deterioro de la detención / apoptosis de G1).
- Sorprendentemente, p53(25,26) mantuvo una actividad significativa en la senescencia y la supresión tumoral.
- Un mutante muerto de transactivación (p53(25,26,53,54)) perdió toda la senescencia y las capacidades de supresión de tumores, similar a la nullicigosidad de p53.
Conclusiones:
- La transactivación eficiente de la mayoría de los objetivos conocidos de p53 no es necesaria para la senescencia y la supresión tumoral.
- La transactivación de p53 es esencial para la supresión tumoral, actuando a través de un conjunto distinto de nuevos genes diana.
- Estos hallazgos diferencian los roles de p53 en la respuesta al daño del ADN frente a la supresión del tumor, ayudando al desarrollo terapéutico.
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