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.

Para ver el artículo completo, pulse aqui

Más artículos en la revista SEBBM.

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio Fisher Scientific, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

Physical proximity of chromatin to nuclear pores prevents harmful R loop accumulation contributing to maintain genome stability

01-11-2017

During transcription, the mRNA may hybridize with DNA, forming an R loop, which can be physiological or pathological, constituting in this case a source of genomic instability. To understand the...

Leer más

Whi7 is an unstable cell-cycle repressor of the Start transcriptional program

01-10-2017

Start is the main decision point in eukaryotic cell cycle in which cells commit to a new round of cell division. It involves the irreversible activation of a transcriptional program...

Leer más

CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation

01-09-2017

In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves...

Leer más

Catalytic Cycle of the N-Acetylglucosaminidase NagZ from Pseudomonas aeruginosa

01-08-2017

The N-acetylglucosaminidase NagZ of Pseudomonas aeruginosa catalyzes the first cytoplasmic step in recycling of muropeptides, cell-wall-derived natural products. This reaction regulates gene expression for the β-lactam resistance enzyme, β-lactamase. The...

Leer más

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice.

01-07-2017

CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits...

Leer más

Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver

01-06-2017

The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific amplifiers of...

Leer más

Programmed mitophagy is essential for the glycolytic switch during cell differentiation

01-05-2017

Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis-associated mouse RGC differentiation depends on mitophagy...

Leer más

Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

01-04-2017

The Bcl-2 (B-cell lymphoma 2) protein Bax (Bcl-2 associated X, apoptosis regulator) can commit cells to apoptosis via outer mitochondrial membrane permeabilization. Bax activity is controlled in healthy cells by...

Leer más

Histone chaperone activity of Arabidopsis thaliana NRP1 is blocked by cytochrome c

01-03-2017

Higher-order plants and mammals use similar mechanisms to repair and tolerate oxidative DNA damage. Most studies on the DNA repair process have focused on yeast and mammals, in which histone...

Leer más

The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes

01-02-2017

The thermogenic activity of brown adipose tissue (BAT) and browning of white adipose tissue are important components of energy expenditure. Here we show that GPR120, a receptor for polyunsaturated fatty...

Leer más

Socios Protectores