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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
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Las interacciones proteína-ADN in vivo en un elemento de respuesta glucocorticoide requieren la presencia de la
Nature
|December 18, 1986
Resumen
Las hormonas glucocorticoides activan la expresión génica a través de la unión al ADN. Este estudio muestra que el receptor glucocorticoide interactúa con los sitios de unión al ADN sólo después del tratamiento hormonal, no antes.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Endocrinología Endocrinología.
- Genética La genética.
Sus antecedentes:
- Las hormonas glucocorticoides regulan la expresión génica a través de la unión del receptor a secuencias específicas de ADN (elementos sensibles a los glucocorticoides, GREs).
- Un modelo prevaleciente sugiere que los receptores citoplasmáticos se translocan al núcleo tras la unión hormonal, aumentando la afinidad del ADN.
- Estudios recientes indican que otros receptores de esteroides son nucleares incluso sin ligando, lo que lleva a investigar el comportamiento del receptor de glucocorticoides.
Objetivo del estudio:
- Para investigar si el receptor libre de glucocorticoides interactúa con su sitio de unión al ADN in vivo antes de la unión hormonal.
- Examinar el papel de la unión hormonal en la interacción in vivo del receptor glucocorticoide con las GREs.
Principales métodos:
- Se empleó la técnica de huella genómica para detectar en vivo las interacciones proteína-ADN.
- La reactividad del dimetilsulfato se utilizó para evaluar los cambios en la unión receptor-ADN.
- Se realizaron experimentos en células de hepatoma (que expresan el gen de la tirosina aminotransferasa, TAT) y células de fibroblastos (que no expresan TAT).
- También se realizaron ensayos in vitro utilizando ADN clonado y receptor parcialmente purificado.
Principales resultados:
- Los cambios en las interacciones proteína-ADN in vivo dentro de los GREs del gen TAT se detectaron solo después del tratamiento hormonal en células de hepatoma.
- No se observaron tales cambios en las células fibroblásticas, que se correlacionan con la ausencia de expresión del gen TAT.
- Muchos de los cambios observados in vivo en la reactividad del dimetilsulfato fueron replicados in vitro con ADN clonado y receptor purificado.
Conclusiones:
- La unión hormonal es esencial para la interacción in vivo del receptor glucocorticoide con su sitio de unión al ADN (GREs) en el gen de la tirosina aminotransferasa.
- Los hallazgos desafían la noción de receptores pre-unidos, transcripcionalmente activos en ausencia de hormona para este sistema específico.
- El estudio destaca la importancia de los cambios conformacionales inducidos por las hormonas para la participación del receptor-ADN en la activación transcripcional.
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