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Un modelo unificador para la regulación mediada por mTORC1 de la traducción del ARNm

Carson C Thoreen¹, Lynne Chantranupong, Heather R Keys

¹Department of Cancer Biology, Dana Farber Cancer Institute, 250 Longwood Avenue, Boston, Massachusetts 02115, USA.

|May 4, 2012

Resumen

El objetivo mamífero del complejo de rapamicina 1 (mTORC1) controla selectivamente la traducción de los ARN mensajeros (ARNm) con motivos de oligopirimidina (TOP) terminal 5'. Esta regulación está mediada por las proteínas de unión 4E (4E-BPs) y eIF4G1, que afectan el crecimiento celular.

Área de la Ciencia:

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

Sus antecedentes:

El objetivo mecanicista de la vía del complejo 1 de rapamicina (mTOR) (mTORC1) es crucial para el crecimiento y la proliferación celular.
mTORC1 regula la traducción del ARN mensajero (ARNm), pero los mecanismos específicos y las dianas del ARNm aún no se comprenden por completo.
Los modelos existentes no explican completamente cómo mTORC1 controla diferencialmente la traducción de ARNm específicos.

Objetivo del estudio:

Para definir las características y mecanismos del ARNm subyacentes al control de traducción dependiente del mTORC1.
Para aclarar el papel de los reguladores de la traducción en el control de mTORC1 de la traducción de ARNm.
Establecer un modelo unificador para la regulación del programa de traducción por parte de mTORC1.

Principales métodos:

El perfil de ribosomas a escala de transcriptoma de alta resolución se empleó en células de ratón.
Las células fueron tratadas agudamente con Torin 1, un potente inhibidor de mTORC1.
Identificación de la oligopirimidina terminal 5' (TOP) y de los motivos similares a TOP en los ARNm regulados.

Principales resultados:

mTORC1 regula selectivamente los ARNm que poseen motivos de oligopirimidina (TOP) de 5' terminal o motivos similares a TOP no reconocidos anteriormente.
No se encontró evidencia que respalde la regulación basada en la longitud o complejidad de la región 5' no traducida.
La pérdida de las proteínas de unión 4E (4E-BPs) hizo que TOP y el ARNm de traducción TOP-like fueran resistentes a la inhibición de mTORC1.
Las 4E-BPs inhiben la iniciación de la traducción al interrumpir la interacción eIF4E-eIF4G1, afectando selectivamente la unión del ARNm TOP.

Conclusiones:

El control de traducción de mTORC1 se dirige principalmente a los ARNm con motivos TOP o similares a TOP.
La familia 4E-BP de represores traslacionales son efectores clave de mTORC1 en la regulación de la traducción del ARNm TOP.
La interacción entre 4E-BPs y eIF4G1 es crítica para la supresión selectiva de mTORC1 de la traducción del ARNm TOP.

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