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dc.contributor.authorHu-He, Kai Hui-
dc.contributor.authorLorenzo, Petra Isabel-
dc.contributor.authorJiménez-Moreno, Carmen M.-
dc.contributor.authorVallejo-Ortega, Jorge-
dc.contributor.authorGauthier, Benoit R.-
dc.date.accessioned2012-06-11T08:04:04Z-
dc.date.available2012-06-11T08:04:04Z-
dc.date.issued2011-06-
dc.identifierissn: 0012-1797-
dc.identifiere-issn: 1939-327X-
dc.identifier.citationDiabetes 60(6): 1705-1715 (2011)-
dc.identifier.urihttp://hdl.handle.net/10261/51150-
dc.descriptionet al.-
dc.description.abstract[Objective]: To establish the role of the transcription factor Pax4 in pancreatic islet expansion and survival in response to physiological stress and its impact on glucose metabolism, we generated transgenic mice conditionally and selectively overexpressing Pax4 or a diabetes-linked mutant variant (Pax4R129W) in β-cells. [Research and Methods]: Glucose homeostasis and β-cell death and proliferation were assessed in Pax4- or Pax4R129W-overexpressing transgenic animals challenged with or without streptozotocin. Isolated transgenic islets were also exposed to cytokines, and apoptosis was evaluated by DNA fragmentation or cytochrome C release. The expression profiles of proliferation and apoptotic genes and β-cell markers were studied by immunohistochemistry and quantitative RT-PCR. [Results]: Pax4 but not Pax4R129W protected animals against streptozotocin-induced hyperglycemia and isolated islets from cytokine-mediated β-cell apoptosis. Cytochrome C release was abrogated in Pax4 islets treated with cytokines. Interleukin-1β transcript levels were suppressed in Pax4 islets, whereas they were increased along with NOS2 in Pax4R129W islets. Bcl-2, Cdk4, and c-myc expression levels were increased in Pax4 islets while MafA, insulin, and GLUT2 transcript levels were suppressed in both animal models. Long-term Pax4 expression promoted proliferation of a Pdx1-positive cell subpopulation while impeding insulin secretion. Suppression of Pax4 rescued this defect with a concomitant increase in pancreatic insulin content. [Conclusions]: Pax4 protects adult islets from stress-induced apoptosis by suppressing selective nuclear factor-κB target genes while increasing Bcl-2 levels. Furthermore, it promotes dedifferentiation and proliferation of β-cells through MafA repression, with a concomitant increase in Cdk4 and c-myc expression.-
dc.description.sponsorshipThis work was funded by the Swiss National Science Foundation (grants 310030-119763 to B.R.G.; 310000-116750/1 to C.B.W. and B.R.G.; 310000-109402, 310000-122423, and CR32I3-129987 to P.M.; and 3100A0103867 NCCR “Frontiers-in-Genetics” to P.L.H.), the Juvenile Diabetes Research Foundation (grants 7-2005-1158 to C.B.W. and B.R.G.; 40-2011-11 to P.M.; and 26-2007-928 and 26-2008-640 to P.L.H.), the EU (FP-7, BETAIMAGE 222980, IMI IMIDIA, and C2008-T7 to P.M. and FP-6, β Cell Therapy Consortium to P.L.H.), the National Institutes of Health/National Institutes of Diabetes and Digestive and Kidney Diseases (the Beta Cell Biology Consortium to P.L.H.), and the Foundation Progreso y Salud, Junta de Andalucia (to B.R.G.). K.H.H.H. was supported by a GeMet/Novo Nordisk fellowship. No other potential conflicts of interest relevant to this article were reported.-
dc.language.isoeng-
dc.publisherAmerican Diabetes Association-
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/222980-
dc.rightsopenAccess-
dc.titleIn vivo conditional pax4 overexpression in mature islet β-cells prevents stress-induced hyperglycemia in mice-
dc.typeartículo-
dc.identifier.doi10.2337/db10-1102-
dc.relation.publisherversionhttp://dx.doi.org/10.2337/db10-1102-
dc.date.updated2012-06-11T08:04:04Z-
dc.description.versionPeer Reviewed-
dc.rights.licensehttp://creativecommons.org/licenses/by-
dc.contributor.funderEuropean Commission-
dc.contributor.funderSwiss National Science Foundation-
dc.contributor.funderJuvenile Diabetes Research Foundation International-
dc.contributor.funderNational Institutes of Health (US)-
dc.contributor.funderNovo Nordisk Foundation-
dc.contributor.funderJunta de Andalucía-
dc.contributor.funderFundación Progreso y Salud-
dc.relation.csicSí-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100000901es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100000002es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100011011es_ES
dc.identifier.pmid21521872-
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
item.languageiso639-1en-
item.fulltextWith Fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.grantfulltextopen-
item.openairetypeartículo-
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