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Un interruptor de transcripción mediado por la metilación del cofactor.
1Gene Expression Laboratory, Department of Biological Chemistry, University of California Davis Cancer Center/Basic Science, Sacramento, CA 95817, USA.
Science (New York, N.Y.)
|November 10, 2001
Resumen
La metilación controlada de proteínas como las proteínas de unión a CREB (CBP) /p300 actúa como un interruptor molecular. Esta metilación del cofactor regula la activación génica en las vías de señalización hormonal.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- La epigenética es la epigenética.
- Regulación genética Reglamento genético.
Sus antecedentes:
- Los cofactores de transcripción CREB-binding proteins (CBP) /p300 juegan un papel crucial en la activación de los genes.
- Estos cofactores poseen un dominio KIX esencial para el reclutamiento de factores de transcripción como CREB.
- Las modificaciones posteriores a la traducción, como la metilación, son cada vez más reconocidas como mecanismos reguladores clave.
Objetivo del estudio:
- Investigar el papel de la metilación en la regulación de la función de CBP/p300.
- Aclarar el mecanismo por el cual la arginina metiltransferasa 1 (CARM1) asociada al coactivador afecta la activación de CREB.
- Definir la metilación del cofactor como un nuevo mecanismo regulador en la señalización hormonal.
Principales métodos:
- Se llevaron a cabo experimentos in vivo e in vitro.
- Se utilizó la mutagenesis dirigida al sitio para identificar el sitio de metilación en CBP/p300.
- Se realizaron ensayos para evaluar la interacción entre CBP/p300 y CREB, y el efecto de la metilación mediada por CARM1.
Principales resultados:
- Un residuo específico de arginina en el dominio KIX de CBP/p300 fue identificado como un sitio de metilación.
- La metilación de este sitio por CARM1 inhibe la interacción entre el dominio KIX y el dominio inducible por quinasa (KID) de CREB.
- CARM1 funciona como un represor en la señalización del monofosfato de adenosina cíclica (cAMP) pero como un activador para la señalización de la hormona nuclear.
Conclusiones:
- La metilación del cofactor, específicamente por CARM1, actúa como un interruptor molecular que controla la transcripción génica.
- La metilación de la histona juega un papel importante en la activación de genes inducida por hormonas.
- La metilación del cofactor representa un mecanismo regulador recientemente identificado dentro de las vías de señalización hormonal.
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