MKP-1 mediates glucocorticoid-induced ERK1/2 dephosphorylation and reduction in pancreatic ß-cell proliferation in islets from early lactating mothers.
Maternal 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 phospho-ERK1/2 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.
Nicoletti-Carvalho
José E
JE
Lineu Prestes Av., São Paulo, SP, Brazil.
Lellis-Santos
Camilo
C
Yamanaka
Tatiana S
TS
Nogueira
Tatiane C
TC
Caperuto
Luciana C
LC
Leite
Adriana R
AR
Anhê
Gabriel F
GF
Bordin
Silvana
S
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007774:Lactation / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats
D005938:Glucocorticoids; D003907:Dexamethasone; D048049:Extracellular Signal-Regulated MAP Kinases; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat