Reference

naturensp 420Nature Medicine 22, 91–96 (2016); PMID: 26692333; doi:10.1038/nm.4013

Authors

Bárbara González-Terán, Juan Antonio López, Elena Rodríguez, Luis Leiva, Sara Martínez-Martínez, Juan Antonio Bernal, Luis Jesús Jiménez-Borreguero, Juan Miguel Redondo, Jesús Vazquez y Guadalupe Sabio

Abstract

Disrupted organ growth leads to disease development. Hypertrophy underlies postnatal heart growth and is triggered after stress, but the molecular mechanisms involved in these processes are largely unknown. Here we show that cardiac activation of p38γ and p38δ increases during postnatal development and by hypertrophy-inducing stimuli. p38γ/δ promote cardiac hypertrophy by phosphorylating the mTORC1 and mTORC2 inhibitor DEPTOR, which leads to its degradation and mTOR activation. Hearts from mice lacking one or both kinases are below normal size, have high levels of DEPTOR, low activity of the mTOR pathway and reduced protein synthesis. The phenotype of p38γ/δ−/− mice is reverted by overactivation of mTOR with amino acids, shRNA-mediated knockdown of Deptor, or cardiomyocyte overexpression of active p38γ and p38δ. Moreover, in WT mice, heart weight is reduced by cardiac overexpression of DEPTOR. Our results demonstrate that p38γ/δ control heart growth by modulating mTOR pathway through DEPTOR phosphorylation and subsequent degradation.

Description

Alcanzar un tamaño apropiado del corazón es esencial para mantener la homeostasis del organismo, alteraciones en su crecimiento puede derivar en el desarrollo de cardiomiopatías. Este trabajo muestra que dos proteínas quinasa activadas por estrés, p38γ/δ, promueven el crecimiento hipertrófico del corazón a través de la fosforilación de la proteína inhibidora de la vía mTOR, DEPTOR. La fosforilación de DEPTOR induce su degradación y la subsecuente activación de mTOR que promoviendo la síntesis protéica y el crecimiento hipertrófico de los cardiomiocitos. Ratones que carecen de p38γ/δ poseen un corazón más pequeño incapaz de responder a señales de hipertrofia como la angiotensina.

 

SabioyGonzález

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Guadalupe Sabio investiga la implicación de las quinasas del estrés (JNK y p38MAPK) en el desarrollo de enfermedades inducidas por la obesidad (cáncer hepático, diabetes y enfermedades cardiovasculares). En su investigación utiliza diversos modelos animales de enfermedad, en combinación con ratones whole body knockout y específicos de tejido. Su interés es conocer los mecanismos por los que estas quinasas pueden afectar al desarrollo de la enfermedad y la posibilidad de utilizarlas como dianas terapéuticas.

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

01-12-2017

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

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...

Read more

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...

Read more

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...

Read more

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...

Read more

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...

Read more

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...

Read more

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...

Read more

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...

Read more

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...

Read more

Protector Members