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.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase

30-04-2020

Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the...

Read more

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

31-03-2020

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT 178R ↓S. FGF23 regulates phosphate homeostasis and deficiency in GALNT3...

Read more

Identification of distinct maturation steps involved in human 40S ribosomal subunit biosynthesis

29-02-2020

Technical problems intrinsic to the purification of preribosome intermediates have limited our understanding of ribosome biosynthesis in humans. Addressing this issue is important given the implication of this biological process...

Read more

Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis

23-01-2020

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of...

Read more

Mip6 binds directly to the Mex67 UBA domainto maintain low levels of Msn2/4 stress-dependent mRNAs

23-12-2019

RNA-binding proteins (RBPs) participate in all steps of gene expression, underscoring their potential as regulators of RNA homeostasis. We structurally and functionally characterize Mip6, a four-RNA recognition motif (RRM)-containing RBP...

Read more

A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis

01-12-2019

Plasmalogens are glycerophospholipids with a hallmark sn-1 vinyl ether bond. These lipids are found in animals and some bacteria and have proposed membrane organization, signaling, and antioxidant roles. We discovered...

Read more

The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature

01-11-2019

Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper...

Read more

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt

01-10-2019

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create...

Read more

Structure–Function of MamC Loop and Its Effect on the *in Vitro* Precipitation of Biomimetic Magnetite Nanoparticles

01-09-2019

MamC, an integral protein of the magnetosome membrane, has recently been proposed as a strong candidate to produce biomimetic (magnetosome-like) magnetite nanoparticles that could be used as an alternative to...

Read more

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Read more

Protector Members