Portada Febrero HepatologyHepatology. 2016 Feb;63(2):604-19. doi: 10.1002/hep.28134. Epub 2015 Oct 10


Judit López-Luque, Daniel Caballero-Díaz, Adoración Martinez-Palacián, César Roncero, Joaquim Moreno-Càceres, María García-Bravo, Esther Grueso, Almudena Fernández, Eva Crosas-Molist, María García-Álvaro, Annalisa Addante, Esther Bertran, Angela M. Valverde, Águeda González-Rodríguez, Blanca Herrera, Lluis Montoliu, Teresa Serrano, Jose-Carlos Segovia, Margarita Fernández, Emilio Ramos, Aránzazu Sánchez, Isabel Fabregat.


Different data support a role for the epidermal growth factor receptor (EGFR) pathway during liver regeneration and hepatocarcinogenesis. However, important issues, such as the precise mechanisms mediating its actions and the unique versus redundant functions, have not been fully defined. Here, we present a novel transgenic mouse model expressing a hepatocyte-specific truncated form of human EGFR, which acts as negative dominant mutant (ΔEGFR) and allows definition of its tyrosine kinase-dependent functions. Results indicate a critical role for EGFR catalytic activity during the early stages of liver regeneration. Thus, after two-thirds partial hepatectomy, ΔEGFR livers displayed lower and delayed proliferation and lower activation of proliferative signals, which correlated with overactivation of the transforming growth factor-β pathway. Altered regenerative response was associated with amplification of cytostatic effects of transforming growth factor-β through induction of cell cycle negative regulators. Interestingly, lipid synthesis was severely inhibited in ΔEGFR livers after partial hepatectomy, revealing a new function for EGFR kinase activity as a lipid metabolism regulator in regenerating hepatocytes. In spite of these profound alterations, ΔEGFR livers were able to recover liver mass by overactivating compensatory signals, such as c-Met. Our results also indicate that EGFR catalytic activity is critical in the early preneoplastic stages of the liver because ΔEGFR mice showed a delay in the appearance of diethyl-nitrosamine-induced tumors, which correlated with decreased proliferation and delay in the diethyl-nitrosamine-induced inflammatory process. Conclusion: These studies demonstrate that EGFR catalytic activity is critical during the initial phases of both liver regeneration and carcinogenesis and provide key mechanistic insights into how this kinase acts to regulate liver pathophysiology.


Los grupos de investigación liderados por las doctoras Isabel Fabregat (IDIBELL), y Aránzazu Sánchez (UCM), en colaboración con el CIEMAT y el CSIC, han desarrollado un modelo de ratón modificado genéticamente que permite, por primera vez, estudiar de forma específica en los hepatocitos el papel de la actividad catalítica del receptor del factor de crecimiento epidérmico (EGFR). El trabajo, publicado en la revista Hepatology, demuestra, por un lado, que la activación de la vía del EGFR es crucial durante los primeros estadios de la regeneración hepática tras una hepatectomía parcial, viéndose esta retrasada, con baja activación de señales proliferativas y predominio de los mecanismos citostáticos. Por otro lado, la vía del EGFR juega un papel muy relevante en los estadios primarios de aparición de tumores en el hígado, presentando los ratones transgénicos un retraso en la aparición de prenódulos tras la inyección del carcinógeno dietil-nitrosamina (DEN). Este efecto se correlaciona con una menor inflamación, motor de la aparición de la hepatocarcinogenesis.





El grupo de la doctora Isabel Fabregat, actualmente ubicado en el IDIBELL, empezó en la Universidad Complutense de Madrid, estudiando los mecanismos que controlan la proliferación, diferenciación y muerte de las células del hígado durante el desarrollo y la regeneración hepática. De éste surgió el grupo de la doctora Aránzazu Sánchez, que sigue ubicado en la UCM, manteniendo ambos grupos una estrecha colaboración. Una de sus líneas de investigación se ha enfocado al estudio del papel que juega la vía del receptor del EGF (EGFR) en las células hepáticas, sobretodo en relación a la resistencia a la muerte causada por el factor de crecimiento transformante beta (TGF-β). En este contexto, se diseñó este nuevo modelo animal, que puede contribuir al esclarecimiento de la función de la vía del EGFR en la fisiología y patología del hígado.

Descárgate este artículo aquí.

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 Fisher Scientific Prize which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma


CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its...

Read more

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


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...

Read more

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


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...

Read more

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


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...

Read more

Catalytic Cycle of the N-Acetylglucosaminidase NagZ from Pseudomonas aeruginosa


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...

Read more

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


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...

Read more

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


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...

Read more

Programmed mitophagy is essential for the glycolytic switch during cell differentiation


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...

Read more

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


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...

Read more

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


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...

Read more

Protector Members