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El estrés ER desencadena la apoptosis mediante la activación de la proteína Bim Bim solo BH3
Hamsa Puthalakath1, Lorraine A O'Reilly, Priscilla Gunn
1The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Cell
|July 3, 2007
Resumen
El estrés del retículo endoplasmático (ER) desencadena la muerte celular mediante la activación de la proteína Bim. Las nuevas vías que implican la desfosforilación y la inducción transcripcional aclaran los mecanismos de apoptosis inducida por el estrés de la ER.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- El estrés del retículo endoplasmático (ER), causado por proteínas mal plegadas o medicamentos, puede conducir a la muerte celular.
- Los mecanismos precisos que vinculan el estrés ER con la apoptosis, particularmente en enfermedades degenerativas, no se comprenden completamente.
- Bim, una proteína proapoptótica, juega un papel clave en la muerte celular inducida por el estrés y está regulada por varios mecanismos.
Objetivo del estudio:
- Para dilucidar los mecanismos moleculares por los cuales el estrés ER induce apoptosis.
- Investigar el papel y la regulación de Bim en la muerte celular inducida por el estrés en ER.
- Identificar posibles objetivos terapéuticos para las enfermedades relacionadas con el estrés ER.
Principales métodos:
- Utilizó cultivos celulares y modelos de animales enteros para estudiar la apoptosis inducida por el estrés ER.
- Investigó la regulación de los niveles de proteínas Bim y su actividad bajo condiciones de estrés ER.
- Se analizó la participación de la proteína fosfatasa 2A (PP2A) y CHOP-C/EBPalpha en la activación de Bim.
Principales resultados:
- Bim es esencial para la apoptosis inducida por el estrés ER en varios tipos de células e in vivo.
- El estrés ER activa Bim a través de dos nuevas vías: la desfosforilación mediada por PP2A (inhibición de la degradación) y la inducción transcripcional mediada por CHOP-C/EBPalpha.
- La desfosforilación por PP2A previene la ubiquitinación de Bim y la degradación proteasómica, mientras que CHOP-C/EBPalpha aumenta directamente la transcripción de Bim.
Conclusiones:
- El estudio define las vías moleculares a través de las cuales el estrés ER desencadena la apoptosis a través de Bim.
- Estos hallazgos revelan PP2A y CHOP-C/EBPalpha como reguladores clave de Bim en el estrés ER.
- Los mecanismos identificados ofrecen posibles objetivos terapéuticos para las enfermedades asociadas con el estrés ER.
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