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La parafibromina/Hyrax activa la transcripción del gen objetivo Wnt/Wg por asociación directa con la
Christian Mosimann1, George Hausmann, Konrad Basler
1National Research Center Frontiers in Genetics, Institut für Molekularbiologie, Universität Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Cell
|April 25, 2006
Resumen
Los investigadores descubrieron que Hyrax / Parafibromina, parte del complejo PAF1, es crucial para la señalización de Wnt. Esta proteína enlaza la beta-catenina con la transcripción génica, revelando un nuevo mecanismo para controlar los genes objetivo de Wnt.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
- Genética La genética.
Sus antecedentes:
- La vía de señalización Wnt regula los procesos celulares fundamentales, incluida la determinación del destino celular, la homeostasis tisular y el desarrollo del cáncer.
- La activación de la vía Wnt implica la unión de la beta-catenina a las proteínas nucleares TCF / LEF, lo que lleva a la transcripción del gen objetivo.
- El mecanismo preciso por el cual la beta-catenina nuclear orquesta el control de la transcripción sigue siendo en gran medida indefinido.
Objetivo del estudio:
- Identificar nuevos componentes de la vía Wnt/Wg que median los resultados transcripcionales de la beta-catenina.
- Para dilucidar el mecanismo molecular a través del cual la beta-catenina nuclear controla la transcripción génica.
Principales métodos:
- Exámenes genéticos en Drosophila para identificar nuevos componentes de la vía Wnt/Wg.
- Pruebas bioquímicas para determinar las interacciones proteína-proteína entre la beta-catenina, Hyrax / Parafibromina y Pygopus.
- Análisis de la activación transcripcional y la expresión génica en respuesta a la modulación de la vía Wnt.
Principales resultados:
- La Drosophila Hyrax y su ortólogo humano, la parafibromina, componentes del complejo del factor asociado a la polimerasa 1 (PAF1), fueron identificados como nuevos componentes de la vía Wnt/Wg.
- Hyrax / Parafibromina se une directamente a la región C-terminal de la beta-catenina / armadillo y es esencial para la translocación nuclear de la señal Wnt / Wg.
- La capacidad de transactivación de Parafibromina/Hyrax depende del reclutamiento de Pygopus a la beta-catenina/Armadillo, estableciendo un vínculo directo entre el complejo de señalización Wnt y el complejo PAF1.
Conclusiones:
- El supresor tumoral parafibromina juega un papel no reconocido anteriormente en la señalización de Wnt.
- Se propone un mecanismo molecular para el control del gen objetivo Wnt, que implica la participación directa del complejo PAF1 por el complejo de señalización nuclear Wnt.
- Esta interacción facilita el control de la iniciación y elongación transcripcional por la ARN polimerasa II, proporcionando nuevos conocimientos sobre la regulación de la vía Wnt.
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