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El PTEN nuclear controla la reparación del ADN y la sensibilidad al estrés genotóxico
1Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
Science (New York, N.Y.)
|July 27, 2013
Resumen
La SUMOilación controla la localización nuclear de PTEN, que es crucial para la respuesta al daño del ADN. La pérdida de PTEN nuclear aumenta la sensibilidad al estrés genotóxico, lo que afecta a las estrategias de terapia del cáncer.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Investigación del cáncer Investigación del cáncer.
- Genética La genética.
Sus antecedentes:
- El homólogo de la fosfatasa y la tensina eliminado en el cromosoma 10 (PTEN) del gen supresor de tumores se pierde con frecuencia en los cánceres humanos.
- El papel citoplasmático de PTEN en la antagonización de la vía de la fosfatidilinositol 3-cinasa (PI3K) está establecido, pero su función nuclear no está clara.
Objetivo del estudio:
- Para investigar el papel de la localización nuclear de PTEN en la respuesta celular al daño del ADN.
- Para aclarar los mecanismos regulatorios que controlan la importación y exportación nuclear de PTEN.
Principales métodos:
- Pruebas de SUMOilación para evaluar la modificación de PTEN.
- Fraccionamiento celular y microscopía para determinar la localización de PTEN.
- Ensayos de sensibilidad al daño del ADN en respuesta al estrés genotóxico.
- Experimentos in vitro e in vivo utilizando modelos con deficiencia de PTEN.
Principales resultados:
- La SUMOilación (SUMO, pequeño modificador similar a la ubiquitina) de PTEN regula su localización nuclear.
- El estrés genotóxico induce una rápida exclusión nuclear de SUMO-PTEN, dependiente de la ataxia telangiectasia mutada (ATM) quinasa.
- Las células que carecen de PTEN nuclear exhiben hipersensibilidad al daño del ADN.
- Las células con deficiencia de PTEN son susceptibles a la matanza por el estrés genotóxico combinado y la inhibición de PI3K.
Conclusiones:
- La localización nuclear de PTEN, controlada por SUMOylation y ATM, es crítica para la respuesta al daño del ADN.
- Dirigirse a la dinámica nuclear de PTEN o combinar la inhibición de PI3K con el estrés genotóxico puede ofrecer nuevas estrategias terapéuticas para los cánceres con deficiencia de PTEN.
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