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.

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