MKP-1 mediates glucocorticoid-induced ERK1/2 dephosphorylation and reduction in pancreatic beta-cell proliferation in islets from early lactating mothers

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dc.contributor.authorNicoletti-Carvalho, Jose E.
dc.contributor.authorLellis-Santos, Camilo
dc.contributor.authorYamanaka, Tatiana S.
dc.contributor.authorNogueira, Tatiane C.
dc.contributor.authorCaperuto, Luciana C. [UNIFESP]
dc.contributor.authorLeite, Adriana R.
dc.contributor.authorAnhe, Gabriel F.
dc.contributor.authorBordin, Silvana
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniversidade Estadual de Campinas (UNICAMP)
dc.date.accessioned2016-01-24T14:05:42Z
dc.date.available2016-01-24T14:05:42Z
dc.date.issued2010-12-01
dc.description.abstractMaternal pancreatic islets undergo a robust increase of mass and proliferation during pregnancy, which allows a compensation of gestational insulin resistance. Studies have described that this adaptation switches to a low proliferative status after the delivery. the mechanisms underlying this reversal are unknown, but the action of glucocorticoids (GCs) is believed to play an important role because GCs counteract the pregnancy-like effects of PRL on isolated pancreatic islets maintained in cell culture. Here, we demonstrate that ERK1/2 phosphorylation (phospho-ERK1/2) is increased in maternal rat islets isolated on the 19th day of pregnancy. Phospho-ERK1/2 status on the 3rd day after delivery (L3) rapidly turns to values lower than that found in virgin control rats (CTL). MKP-1, a protein phosphatase able to dephosphorylate ERK1/2, is increased in islets from L3 rats. Chromatin immunoprecipitation assay revealed that binding of glucocorticoid receptor (GR) to MKP-1 promoter is also increased in islets from L3 rats. in addition, dexamethasone (DEX) reduced phospho-ERK1/2 and increased MKP-1 expression in RINm5F and MIN-6 cells. Inhibition of transduction with cycloheximide and inhibition of phosphatases with orthovanadate efficiently blocked DEX-induced downregulation of phospho-ERK1/2. in addition, specific knockdown of MKP-1 with siRNA suppressed the downregulation of phosphoERK1/2 and the reduction of proliferation induced by DEX. Altogether, our results indicate that downregulation of phospho-ERK1/2 is associated with reduction in proliferation found in islets of early lactating mothers. This mechanism is probably mediated by GC-induced MKP-1 expression.en
dc.description.affiliationUniv São Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508 São Paulo, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biol Sci, Diadema, SP, Brazil
dc.description.affiliationUniv Estadual Campinas, Fac Med Sci, Dept Pharmacol, São Paulo, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biol Sci, Diadema, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Pesquisa
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.format.extentE1006-E1015
dc.identifierhttp://dx.doi.org/10.1152/ajpendo.00341.2010
dc.identifier.citationAmerican Journal of Physiology-endocrinology and Metabolism. Bethesda: Amer Physiological Soc, v. 299, n. 6, p. E1006-E1015, 2010.
dc.identifier.doi10.1152/ajpendo.00341.2010
dc.identifier.issn0193-1849
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/33094
dc.identifier.wosWOS:000285710400017
dc.language.isoeng
dc.publisherAmer Physiological Soc
dc.relation.ispartofAmerican Journal of Physiology-endocrinology and Metabolism
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectmitogen-activated protein kinase phosphatase-1en
dc.subjectextracellular signal-regulated kinase 1/2en
dc.subjectdual-specificity phosphatasesen
dc.subjectpregnancyen
dc.subjectlactationen
dc.titleMKP-1 mediates glucocorticoid-induced ERK1/2 dephosphorylation and reduction in pancreatic beta-cell proliferation in islets from early lactating mothersen
dc.typeinfo:eu-repo/semantics/article
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