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La apoptosis inducida por Ca2+ a través de la desfosforilación de la calcineurina de las BAD
H G Wang1, N Pathan, I M Ethell
1The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science (New York, N.Y.)
|April 9, 1999
Resumen
La proteína fosfatasa activada por calcio calcineurina desencadena la apoptosis mediante la desfosforilación de la proteína pro-apoptótica BAD. Esto conduce a la DABE.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La neurociencia es la neurociencia.
Sus antecedentes:
- Se sabe que la calcineurina, una proteína fosfatasa activada por el calcio, induce la apoptosis.
- Los mecanismos moleculares precisos por los cuales la calcineurina promueve la muerte celular programada permanecen en gran parte sin aclarar.
Objetivo del estudio:
- Para investigar el papel de la calcineurina en la inducción de la apoptosis.
- Para identificar los objetivos y mecanismos posteriores regulados por la calcineurina durante la apoptosis.
Principales métodos:
- Pruebas bioquímicas para evaluar la desfosforilación y heterodimerización de las proteínas.
- Estudios de localización celular utilizando microscopía para rastrear la translocación de proteínas.
- Experimentos en las neuronas del hipocampo que involucran la estimulación del L-glutamato.
- Estudios de inhibición utilizando mutantes de calcineurina dominantes negativos y inhibidores farmacológicos.
Principales resultados:
- La calcineurina desfosforila la proteína pro-apoptótica BAD, un miembro de la familia Bcl-2.
- La desfosforilación mejora la heterodimerización de BAD con Bcl-xL, promoviendo la apoptosis.
- La desfosforilación de BAD inducida por el calcio causa su disociación de las proteínas 14-3-3 y la translocación a las mitocondrias.
- En las neuronas del hipocampo, el L-glutamato desencadena la focalización mitocondrial de BAD y la apoptosis, que son bloqueadas por la inhibición de la calcineurina.
Conclusiones:
- Una nueva vía inducible por calcio para la inducción de la apoptosis implica la regulación mediada por calcineurina de la fosforilación BAD.
- La calcineurina controla la localización de BAD al alterar su estado de fosforilación, lo que lleva a la muerte celular dependiente de las mitocondrias.
- Este mecanismo pone de relieve un papel crítico de la calcineurina en la apoptosis neuronal.
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