Referencia

Nucleic Acids Res. 2015 Sep 22. pii: gkv923.

Autores

María Pilar de Lucas, Alberto G Sáez, Encarnación Lozano.

Resumen

Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells.

Descripción

Aunque los microRNAs (miRNAs) modulen la expresión del 60% de los genes codificantes, suele ser difícil determinar su papel e identificar sus genes diana. En este trabajo, utilizando el organismo modelo Caenorhabditis elegans, se ha podido determinar que la familia de microRNAs (miRNAs) de mir-58 es capaz de regular negativamente la actividad de las rutas de TGFβ mejor conocidas en este nematodo: TGFβ Sma/Mab (regula el tamaño corporal) y TGFβ Dauer (implicada en la entrada en el estadio de resistencia dauer). Esta inhibición por parte de la familia de mir-58 se produce de forma directa sobre el ligando dbl-1 y los receptores daf-1, daf-4 and sma-6 de estas rutas de TGFβ. Adicionalmente, se ha observado un bucle regulatorio negativo entre TGF-β Sma/Mab y los miembros de la familia miR-58 y miR-80. Este estudio sugiere que la interacción entre la familia de mir-58 y genes de la ruta de TGFβ es clave en las decisiones sobre el crecimiento de los animales y la resistencia al estrés en C. elegans y, posiblemente, en otros organismos.

 

UFIEC

 

REFERENCIA DEL GRUPO INVESTIGADOR

Nuestro grupo estaba constituído por su directora, la contratada Ramón y Cajal, Dra. Encarnación Lozano, el Dr. Alberto G. Sáez, y la doctoranda María Pilar de Lucas, además de varios estudiantes de licenciatura en estancias cortas. Formamos parte de la Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), del Instituto de Salud Carlos III. Nuestro trabajo se ha centrado en identificar moduladores de la señalización por TGFβ, contribuyendo así a explicar la versatilidad fenotípica de dicha ruta bioquímica. Para ello utilizamos fundamentalmente el nematodo Caenorhabditis elegans.

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