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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
Los metabolitos del androstano se unen y desactivan el receptor nuclear CAR-beta
B M Forman1, I Tzameli, H S Choi
1The City of Hope National Medical Center, Duarte, California 91010, USA. bforman@gte.net
Nature
|October 23, 1998
Resumen
La actividad del receptor-beta androstano (CAR-beta) constitutivo es inhibida por los esteroides androstanos específicos. Estos esteroides actúan como agonistas inversos, invirtiendo el CAR-beta.
Área de la Ciencia:
- Endocrinología Molecular La Endocrinología Molecular
- Las vías de señalización de esteroides.
- Investigación de los Receptores Nucleares en la Investigación de los Receptores Nucleares.
Sus antecedentes:
- El receptor huérfano CAR-beta (receptor constitutivo androstano-beta) forma heterodímeros con el receptor del retinoide-X.
- El CAR-beta constitutivamente activa la transcripción génica independientemente de la unión del ligando.
- Los receptores nucleares clásicos generalmente requieren la unión de ligandos para la activación transcripcional.
Objetivo del estudio:
- Para investigar el mecanismo detrás de la actividad constitutiva de CAR-beta.
- Para identificar ligandos potenciales que modulan la actividad CAR-beta.
- Caracterizar la naturaleza de los ligandos identificados y su mecanismo de acción.
Principales métodos:
- Detección de posibles ligandos de CAR-beta. para el cribado.
- Evaluación del efecto de los esteroides identificados en la actividad transcripcional constitutiva del CAR-beta.
- Evaluación de la estereospecificidad de la interacción esteroide.
- Analizando el impacto de los esteroides en la heterodimerización CAR-beta, la unión al ADN y el reclutamiento / liberación de coactivadores.
Principales resultados:
- El androstanol y el androstenol fueron identificados como inhibidores de la actividad constitutiva del CAR-beta.
- El efecto inhibidor fue estereospecífico, requiriendo una estructura de androstano 3alfa-hidroxi, 5alfa-reducida.
- Estos androstanos no afectan la heterodimerización o la unión al ADN, pero promueven la liberación del coactivador del CAR-beta.
Conclusiones:
- El CAR-beta funciona a través del reclutamiento de coactivadores independientes de los ligandos.
- Los androstanos específicos actúan como agonistas inversos de origen natural para el CAR-beta.
- Esto define una nueva vía de señalización esteroide que se opone a los mecanismos convencionales de receptores nucleares.
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