Referencia

Mol Cell. 2012 Dec 26. pii: S1097-2765(12)00979-3. doi: 10.1016/j.molcel.2012.11.022. [Epub ahead of print].

Autores

Ana Chocarro-Calvo, Jose Manuel García-Martínez, Soraya Ardila-González, Antonio De la Vieja and Custodia García-Jiménez

Resumen

Nuclear accumulation of β-catenin, a widely recognized marker of poor cancer prognosis, drives cancer cell proliferation and senescence bypass and regulates incretins, critical regulators of fat and glucose metabolism. Diabetes, characterized by elevated blood glucose levels, is associated with increased cancer risk, partly because of increased insulin growth factor 1 signaling, but whether elevated glucose directly impacts cancer-associated signal-transduction pathways is unknown. Here, we show that high glucose is essential for nuclear localization of β-catenin in response to Wnt signaling. Glucose-dependent β-catenin nuclear retention requires lysine 354 and is mediated by alteration of the balance between p300 and sirtuins that trigger β-catenin acetylation. Consequently β-catenin accumulates in the nucleus and activates target promoters under combined glucose and Wnt stimulation, but not with either stimulus alone. Our results reveal a mechanism by which high glucose enhances signaling through the cancer-associated Wnt/β-catenin pathway and may explain the increased frequency of cancer associated with obesity and diabetes.

Descripción

Este trabajo identifica las claves moleculares de uno de los mecanismos por las que la frecuencia de cánceres, tan comunes como el de colon o tan fulminantes como el de páncreas, puede ser hasta el doble en la población diabética según datos epidemiológicos. Hasta ahora se atribuía el hecho a la señalización por IGF-1. Este trabajo demuestra que la retención nuclear de la β-catenina en respuesta a Wnt depende de la integridad de su lisina 354 que se acetila en respuesta a elevados niveles de glucosa pero no niveles fisiológicos. La acetilasa p300 y la desacetilasa SIRT1 median los efectos.

imagen feb

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo liderado por la Dra. Custodia García Jiménez estudia los mecanismos de remodelación de la señalización tumoral por factores ambientales, centrándose en los efectos ejercidos por cambios metabólicos controlables a través de la dieta y el ejercicio. Colaboran estrechamente con el Dr. Antonio de la Vieja Escolar, interesado en la búsqueda de nuevos marcadores y dianas moleculares para desarrollar terapias antitumorales alternativas. Sus investigaciones abarcan cánceres de intestino, páncreas, ovario y tiroides.

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