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dc.contributor.author | Gonzalez-Teran, Barbara | |
dc.contributor.author | Lopez, Juan Antonio | |
dc.contributor.author | Rodriguez, Elena | |
dc.contributor.author | Leiva-Vega, Luis | |
dc.contributor.author | Martinez-Martinez, Sara | |
dc.contributor.author | Bernal, Juan Antonio | |
dc.contributor.author | Jimenez-Borreguero, Luis J. | |
dc.contributor.author | Redondo, Juan Miguel | |
dc.contributor.author | Vazquez, Jesus | |
dc.contributor.author | Sabio, Guadalupe | |
dc.date.accessioned | 2017-10-30T13:32:27Z | |
dc.date.available | 2017-10-30T13:32:27Z | |
dc.date.issued | 2016 | |
dc.identifier | ISI:000369019300005 | |
dc.identifier.citation | Nat Commun. 2016; 7:10477 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/5250 | |
dc.description.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 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.sponsorship | We 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.iso | eng | |
dc.publisher | Nature Publishing Group | |
dc.type.hasVersion | VoR | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | INDUCED CARDIAC-HYPERTROPHY | |
dc.subject | SIGNALING PATHWAYS | |
dc.subject | PRESSURE-OVERLOAD | |
dc.subject | UBIQUITIN LIGASE | |
dc.subject | ANGIOTENSIN-II | |
dc.subject | KINASE PLAYS | |
dc.subject | S6 KINASE | |
dc.subject | P38 | |
dc.subject | MICE | |
dc.subject | CARDIOMYOPATHY | |
dc.title | p38 gamma and delta promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation | |
dc.type | journal article | |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 26795633 | |
dc.format.volume | 7 | |
dc.identifier.doi | 10.1038/ncomms10477 | |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.contributor.funder | Unión Europea. Comisión Europea | |
dc.contributor.funder | European Foundation for the Study of Diabetes | |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | |
dc.contributor.funder | Comunidad de Madrid (España) | |
dc.contributor.funder | Red de Investigación Cardiovascular (RIC) (España) | |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | |
dc.contributor.funder | Fundación La Marató TV3 | |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | |
dc.contributor.funder | Fundación ProCNIC | |
dc.description.peerreviewed | Sí | |
dc.relation.publisherversion | https://doi.org/10.1136/10.1038/ncomms10477 | |
dc.identifier.journal | Nature Communications | |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Papel de las quinasas activadas por el estrés en el desarrollo de enfermedades cardiovasculares, diabetes y cáncer | |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Proteómica cardiovascular | |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Regulación Génica en Remodelado Vascular e Inflamación | |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Cardiomiopatías de origen genético | |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Imagen Cardiovascular y Estudios Poblacionales | |
dc.repisalud.orgCNIC | CNIC::Unidades técnicas::Proteómica / Metabolómica | |
dc.repisalud.institucion | CNIC | |
dc.relation.projectID | MINECO/ICTI2013-2016/SVP-2013-067639 | es_ES |
dc.relation.projectID | MINECO/ICTI2013-2016/SAF2013-43506-R | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/260464 | es_ES |
dc.rights.accessRights | open access | es_ES |