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La dinámica de la actina controla la actividad del SRF mediante la regulación de su coactivador MAL

Francesc Miralles¹, Guido Posern, Alexia-Ileana Zaromytidou

¹Transcription Laboratory, Room 401, Cancer Research UK London Research Institute, Lincolns Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.

|May 7, 2003

Resumen

Las Rho GTPasas controlan el factor de transcripción SRF mediante la regulación de la polimerización de actina. Este estudio revela que la señalización de la Rho-actina dirige la localización nuclear del coactivador de la SRF MAL, un mecanismo clave para la actividad de la SRF.

Área de la Ciencia:

Biología celular Biología celular.
Biología Molecular Biología Molecular
La bioquímica es la bioquímica.

Sus antecedentes:

Las GTPasas Rho son reguladores críticos del citoesqueleto de actina.
El factor de respuesta sérica del factor de transcripción (SRF) controla la expresión génica en respuesta a la dinámica de la actina.
El mecanismo preciso que vincula la señalización de la Rho-actina a la actividad de la SRF, en particular el papel de los coactivadores, sigue siendo elusivo.

Objetivo del estudio:

Para dilucidar el mecanismo por el cual la señalización de Rho-actina regula la actividad de SRF.
Investigar el papel del coactivador de la FRS MAL relacionado con la miocardina en esta vía.
Para caracterizar la regulación de la localización subcelular de MAL por la señalización de Rho-actina.

Principales métodos:

Estudios de localización celular utilizando estimulación sérica y activación de la vía Rho.
Análisis de mutantes MAL para identificar dominios funcionales.
Análisis bioquímicos para evaluar las interacciones MAL-actina.
Inmunoprecipitación de cromatina para identificar promotores objetivo de SRF.

Principales resultados:

La señalización de Rho-actina es necesaria y suficiente para la acumulación nuclear de MAL.
Los motivos RPEL N-terminales del MAL son cruciales para la detección de la señalización de la Rho-actina y la unión de la actina no polimerizada.
Las regiones MAL específicas median la importación nuclear y la retención citoplasmática.
Los mutantes MAL constitutivamente citoplasmáticos interrumpen la regulación del SRF.
MAL se asocia con promotores de genes objetivo de SRF regulados por la señalización de Rho-actina.

Conclusiones:

La señalización de Rho-actina controla la actividad de la SRF mediante la modulación de la localización nuclear del coactivador MAL.
MAL actúa como un sensor directo de la dinámica de la Rho-actina, vinculando los cambios del citoesqueleto a la regulación transcripcional.
Este mecanismo proporciona una nueva visión de cómo las señales extracelulares se transducen al núcleo a través del citoesqueleto de actina.

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