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dc.contributor.authorGonzalez-Teran, Barbara 
dc.contributor.authorLopez, Juan Antonio 
dc.contributor.authorRodriguez, Elena 
dc.contributor.authorLeiva-Vega, Luis 
dc.contributor.authorMartinez-Martinez, Sara 
dc.contributor.authorBernal, Juan Antonio 
dc.contributor.authorJimenez-Borreguero, Luis J. 
dc.contributor.authorRedondo, Juan Miguel 
dc.contributor.authorVazquez, Jesus 
dc.contributor.authorSabio, Guadalupe 
dc.date.accessioned2017-10-30T13:32:27Z
dc.date.available2017-10-30T13:32:27Z
dc.date.issued2016
dc.identifierISI:000369019300005
dc.identifier.citationNat Commun. 2016; 7:10477
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/20.500.12105/5250
dc.description.abstractDisrupted 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 p38 gamma and p38 delta increases during postnatal development and by hypertrophy-inducing stimuli. p38 gamma/delta 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 p38 gamma/delta(-/-) mice is reverted by overactivation of mTOR with amino acids, shRNA-mediated knockdown of Deptor, or cardiomyocyte overexpression of active p38 gamma and p38 delta. Moreover, in WT mice, heart weight is reduced by cardiac overexpression of DEPTOR. Our results demonstrate that p38 gamma/delta control heart growth by modulating mTOR pathway through DEPTOR phosphorylation and subsequent degradation.
dc.description.sponsorshipWe thank S. Bartlett for English editing. We are grateful to Dr R.J. Davis for providing the mammalian expression plasmids for p38 gamma and p38 delta, and to Dr D. Engelberg for providing the constitutively active mutants. We thank Dr D. Sabatini for the mTOR and DEPTOR plasmids, Dr Yeh for the HA-Ubiquitin plasmid and Dr Xiong for the bTrCP and Cul1. Recombinant active p38 proteins were provided by the Division of Signal Transduction Therapy (DSTT), University of Dundee, UK. We are grateful to A.R. Nebreda for his critical reading of the manuscript. We thank the staff at the CNIC Imaging and viral vectors Unit for technical support. G.S. and J.A.B. are investigators of the Ramon y Cajal Program. B.G.-T. is a fellow of the FPI Severo Ochoa CNIC program (SVP-2013-067639). This work was funded by the following grants to G.S.: ERC 260464, EFSD 2030, MICINN SAF2013-43506-R and Comunidad de Madrid S2010/BMD-2326; J.M.R., J.V. and JMR are supported by the Spanish Ministry of Health (Ministerio de Sanidad y Consumo) Red de Investigacion Cardiovascular (RIC) cofounded by FEDER (grants RD06/0042/0022 to J.M.R. and RD12/0042/0056 to J.V.). S.M.-M. is supported by the Fundacion La Marato TV3 (122532). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation.
dc.language.isoeng
dc.publisherNature Publishing Group 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectINDUCED CARDIAC-HYPERTROPHY
dc.subjectSIGNALING PATHWAYS
dc.subjectPRESSURE-OVERLOAD
dc.subjectUBIQUITIN LIGASE
dc.subjectANGIOTENSIN-II
dc.subjectKINASE PLAYS
dc.subjectS6 KINASE
dc.subjectP38
dc.subjectMICE
dc.subjectCARDIOMYOPATHY
dc.titlep38 gamma and delta promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation
dc.typejournal article
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID26795633
dc.format.volume7
dc.identifier.doi10.1038/ncomms10477
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderEuropean Foundation for the Study of Diabetes 
dc.contributor.funderMinisterio de Ciencia e Innovación (España) 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderRed de Investigación Cardiovascular (RIC) (España)
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderFundación La Marató TV3 
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) 
dc.contributor.funderFundación ProCNIC 
dc.description.peerreviewed
dc.relation.publisherversionhttps://doi.org/10.1136/10.1038/ncomms10477
dc.identifier.journalNature Communications
dc.repisalud.orgCNICCNIC::Grupos de investigación::Papel de las quinasas activadas por el estrés en el desarrollo de enfermedades cardiovasculares, diabetes y cáncer
dc.repisalud.orgCNICCNIC::Grupos de investigación::Proteómica cardiovascular
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Génica en Remodelado Vascular e Inflamación
dc.repisalud.orgCNICCNIC::Grupos de investigación::Cardiomiopatías de origen genético
dc.repisalud.orgCNICCNIC::Grupos de investigación::Imagen Cardiovascular y Estudios Poblacionales
dc.repisalud.orgCNICCNIC::Unidades técnicas::Proteómica / Metabolómica
dc.repisalud.institucionCNIC
dc.relation.projectIDMINECO/ICTI2013-2016/SVP-2013-067639es_ES
dc.relation.projectIDMINECO/ICTI2013-2016/SAF2013-43506-Res_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/260464es_ES
dc.rights.accessRightsopen accesses_ES


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Atribución 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Atribución 4.0 Internacional