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dc.contributor.CRUESPUniversidade Estadual de Campinaspt_BR
dc.typeArtigo de periódicopt_BR
dc.titleRapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutationpt_BR
dc.contributor.authorMarin, TMpt_BR
dc.contributor.authorKeith, Kpt_BR
dc.contributor.authorDavies, Bpt_BR
dc.contributor.authorConner, DApt_BR
dc.contributor.authorGuha, Ppt_BR
dc.contributor.authorKalaitzidis, Dpt_BR
dc.contributor.authorWu, Xpt_BR
dc.contributor.authorLauriol, Jpt_BR
dc.contributor.authorWang, Bpt_BR
dc.contributor.authorBauer, Mpt_BR
dc.contributor.authorBronson, Rpt_BR
dc.contributor.authorFranchini, KGpt_BR
dc.contributor.authorNeel, BGpt_BR
dc.contributor.authorKontaridis, MIpt_BR
unicamp.authorKontaridis, Maria I. Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiol, Ctr Life Sci, Boston, MA 02115 USApt_BR
unicamp.authorMarin, Talita M. Franchini, Kleber G. Univ Estadual Campinas, Sch Med, Dept Internal Med, Campinas, SP, Brazilpt_BR
unicamp.authorConner, David A. Harvard Univ, Sch Med, Dept Genet, Boston, MA USApt_BR
unicamp.authorConner, David A. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USApt_BR
unicamp.authorKalaitzidis, Demetrios Childrens Hosp, Dept Hematol Oncol, Boston, MA 02115 USApt_BR
unicamp.authorWu, Xue Neel, Benjamin G. Univ Toronto, Dept Med Biophys, Toronto, ON, Canadapt_BR
unicamp.authorWu, Xue Neel, Benjamin G. Ontario Canc Inst, Campbell Family Canc Res Inst, Toronto, ON M4X 1K9, Canadapt_BR
unicamp.authorWu, Xue Neel, Benjamin G. Univ Hlth Network, Princess Margaret Hosp, Toronto, ON, Canadapt_BR
unicamp.authorBauer, Michael Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USApt_BR
unicamp.authorBronson, Roderick Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USApt_BR
unicamp.authorKontaridis, Maria I. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USApt_BR
dc.subject.wosTyrosine-phosphatase Shp-2pt_BR
dc.subject.wosCause Noonan-syndromept_BR
dc.subject.wosInduced Cardiac-hypertrophypt_BR
dc.subject.wosChronic Pressure-overloadpt_BR
dc.subject.wosActivated Protein-kinasept_BR
dc.subject.wosOf-function Mutationspt_BR
dc.subject.wosSignaling Pathwayspt_BR
dc.description.abstractLEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11(Y279C/+) (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS
dc.relation.ispartofJournal Of Clinical Investigationpt_BR
dc.relation.ispartofabbreviationJ. Clin. Invest.pt_BR
dc.publisher.cityAnn Arborpt_BR
dc.publisherAmer Soc Clinical Investigation Incpt_BR
dc.identifier.citationJournal Of Clinical Investigation. Amer Soc Clinical Investigation Inc, v. 121, n. 3, n. 1026, n. 1043, 2011.pt_BR
dc.sourceWeb of Sciencept_BR
dc.description.sponsorshipNIH [HL088514, HL083273]pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipFrederick Banting and Charles Best Canada Graduate Scholarshippt_BR
dc.description.sponsorshipMilton Fundpt_BR
dc.description.sponsorshipBeth Israel Deaconess Medical Center Division of Cardiologypt_BR
dc.description.sponsorshipOntario Ministry of Health and Long-Term Carept_BR
dc.description.sponsorship1Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsordocumentnumberNIH [HL088514, HL083273]pt
dc.description.sponsordocumentnumberFAPESP [2006/55920]pt
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