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La fosforilación dependiente de CDK2 de FOXO1 como una respuesta apoptótica al daño del ADN
Haojie Huang1, Kevin M Regan, Zhenkun Lou
1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Science (New York, N.Y.)
|October 14, 2006
Resumen
La cinasa 2 dependiente de ciclina (CDK2) regula la supervivencia celular después del daño del ADN mediante el control de la actividad del factor de transcripción FOXO1. El daño en el ADN inhibe la CDK2, impidiendo la fosforilación de FOXO1 y promoviendo la muerte celular.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
- Genética La genética.
Sus antecedentes:
- La actividad de la cinasa 2 dependiente de la ciclina (CDK2) generalmente se inhibe después del daño del ADN, crucial para la detención del ciclo celular y la reparación del ADN.
- El papel de CDK2 en la supervivencia celular bajo estrés genotóxico sigue sin estar claro, a pesar de la importancia conocida de los factores de transcripción Forkhead box O (FOXO) en la supervivencia celular.
Objetivo del estudio:
- Investigar la interacción funcional entre CDK2 y FOXO1 en la regulación de la supervivencia celular después del daño del ADN.
- Para aclarar el mecanismo por el cual CDK2 influye en la actividad de FOXO1 y la posterior muerte celular apoptótica.
Principales métodos:
- Ensayos de fosforilación in vitro e in vivo para determinar la fosforilación mediada por CDK2 de FOXO1 en la serina-249 (Ser249).
- Pequeño ARN interferente (siRNA) para silenciar la expresión de FOXO1 y evaluar su impacto en la muerte celular inducida por daño al ADN.
- Restauración de la expresión de FOXO1 para confirmar el papel de la fosforilación de Ser249 en la supervivencia celular.
Principales resultados:
- CDK2 fosforila específicamente FOXO1 en Ser249, lo que lleva a su localización e inhibición en el citoplasma.
- El daño en el ADN anula la fosforilación de CDK2-FOXO1 a través de la vía de punto de control del ciclo celular dependiente de Chk1/Chk2.
- El silenciamiento de FOXO1 reduce la muerte celular inducida por daño al ADN, un efecto reversible mediante la restauración de la expresión de FOXO1 dependiente de la fosforilación de Ser249.
Conclusiones:
- La interacción funcional entre CDK2 y FOXO1 proporciona un nuevo mecanismo para regular la muerte celular apoptótica en respuesta a las rupturas de la cadena de ADN.
- La fosforilación mediada por CDK2 de FOXO1 es un determinante crítico de la supervivencia o muerte celular después del estrés genotóxico.
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