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La vida útil funcional del coactivador SRC-3 está regulada por un reloj de tiempo de ubiquitina fosfodependiente
Ray-Chang Wu1, Qin Feng, David M Lonard
1Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cell
|June 19, 2007
Resumen
La ubiquitinación regulada de SRC-3 (coactivador del receptor de esteroides-3) controla su activación y degradación. Este proceso dependiente de la fosforilación actúa como un "reloj de tiempo de transcripción", equilibrando la función del coactivador y previniendo la oncogénesis.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
- Investigación del cáncer Investigación del cáncer.
Sus antecedentes:
- SRC-3 (Steroid Receptor Coactivator-3) / AIB1 es un coactivador crucial del crecimiento implicado en la oncogénesis cuando está sobreactivado.
- La regulación estricta de la actividad de SRC-3 es esencial para la función celular normal y la prevención del crecimiento incontrolado.
Objetivo del estudio:
- Aclarar los mecanismos reguladores que rigen la activación del coactivador SRC-3 y la especificidad transcripcional.
- Investigar el papel de la ubiquitinación dependiente de la fosforilación en el control de la función y la estabilidad del SRC-3.
Principales métodos:
- Identificación de un elemento crítico "actrón/degrón" dentro del SRC-3.
- Caracterización de GSK3 como la quinasa responsable y SCF ((Fbw7alpha) como la E3 ubiquitina ligasa.
- Análisis de los patrones de ubiquitinación SRC-3 (multi-/mono-ubiquitinación frente a poliubiquitinación) y sus consecuencias funcionales.
Principales resultados:
- Descubrió una vía de ubiquitinación dependiente de la fosforilación que regula el SRC-3.
- GSK3 y SCF ((Fbw7alpha) identificados en esta cascada reguladora.
- Se demostró que SCF ((Fbw7alpha) media tanto en la activación no proteolítica como en la degradación proteasómica de SRC-3.
- Se observó un proceso de ubiquitinación bifásica que pasa de la activación a la degradación, actuando como un "reloj de tiempo transcripcional".
Conclusiones:
- La fosforilación coordinada y la ubiquitinación regulan estrictamente la actividad y la vida útil de SRC-3.
- La ubiquitinación de SRC-3 es un evento bifásico que controla la activación y degradación del coactivador.
- Este mecanismo regulador asegura un control preciso de la coactivación transcripcional y previene la sobreactivación oncogénica.
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