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.

[1]  L. Velloso,et al.  UPR-mediated TRIB3 expression correlates with reduced AKT phosphorylation and inability of interleukin 6 to overcome palmitate-induced apoptosis in RINm5F cells. , 2010, The Journal of endocrinology.

[2]  R. Curi,et al.  Smad5 regulates Akt2 expression and insulin-induced glucose uptake in L6 myotubes , 2010, Molecular and Cellular Endocrinology.

[3]  W. Gong,et al.  Glucocorticoids inhibit IL-1beta-induced GM-CSF expression at multiple levels: roles for the ERK pathway and repression by MKP-1. , 2010, The Biochemical journal.

[4]  Kyong-Heon Kim,et al.  Ginsenoside Rg3 Suppresses Palmitate-Induced Apoptosis in MIN6N8 Pancreatic β-Cells , 2009, Journal of clinical biochemistry and nutrition.

[5]  Sanjeev Kumar,et al.  Dexamethasone ameliorates renal ischemia-reperfusion injury. , 2009, Journal of the American Society of Nephrology : JASN.

[6]  J. Cross,et al.  Prolactin receptor is required for normal glucose homeostasis and modulation of beta-cell mass during pregnancy. , 2009, Endocrinology.

[7]  K. Patterson,et al.  Dual-specificity phosphatases: critical regulators with diverse cellular targets. , 2009, The Biochemical journal.

[8]  A. Boschero,et al.  Islet neogenesis-associated protein signaling in neonatal pancreatic rat islets: involvement of the cholinergic pathway. , 2008, The Journal of endocrinology.

[9]  M. Blandino-Rosano,et al.  Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1. , 2008, Journal of molecular endocrinology.

[10]  R. Sorenson,et al.  Beneficial effects of lipids and prolactin on insulin secretion and beta-cell proliferation: a role for lipids in the adaptation of islets to pregnancy. , 2008, The Journal of endocrinology.

[11]  F. Lang,et al.  IGF-1 Protects Against Dexamethasone-Induced Cell Death in Insulin Secreting INS-1 Cells Independent of AKT/PKB Phosphorylation , 2008, Cellular Physiology and Biochemistry.

[12]  L. Kremer,et al.  Mycobacterial lipomannan induces MAP kinase phosphatase‐1 expression in macrophages , 2008, FEBS letters.

[13]  P. Hulley,et al.  Mitogen-activated protein kinase phosphatase 1/dual specificity phosphatase 1 mediates glucocorticoid inhibition of osteoblast proliferation. , 2007, Molecular endocrinology.

[14]  A. Boschero,et al.  Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period. , 2007, The Journal of endocrinology.

[15]  R. Curi,et al.  Postpartum glycemic homeostasis in early lactating rats is accompanied by transient and specific increase of soleus insulin response through IRS2/AKT pathway. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[16]  J. Pouysségur,et al.  The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition , 2007, Oncogene.

[17]  R. Dickinson,et al.  Diverse physiological functions for dual-specificity MAP kinase phosphatases , 2006, Journal of Cell Science.

[18]  C. Tickle,et al.  Negative feedback predominates over cross‐regulation to control ERK MAPK activity in response to FGF signalling in embryos , 2006, FEBS letters.

[19]  L. Velloso,et al.  Participation of prolactin receptors and phosphatidylinositol 3-kinase and MAP kinase pathways in the increase in pancreatic islet mass and sensitivity to glucose during pregnancy. , 2004, The Journal of endocrinology.

[20]  Ming-Ming Zhou,et al.  Structure and regulation of MAPK phosphatases. , 2004, Cellular signalling.

[21]  Teiji Wada,et al.  Mitogen-activated protein kinases in apoptosis regulation , 2004, Oncogene.

[22]  J. Friedman,et al.  Prolactin, progesterone, and dexamethasone coordinately and adversely regulate glucokinase and cAMP/PDE cascades in MIN6 beta-cells. , 2004, American journal of physiology. Endocrinology and metabolism.

[23]  Masato Ogata,et al.  Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells. , 2003, Diabetes.

[24]  A. Clark,et al.  Crosstalk between glucocorticoids and mitogen-activated protein kinase signalling pathways. , 2003, Current opinion in pharmacology.

[25]  J. Carvalheira,et al.  Prolactin-Signal Transduction in Neonatal Rat Pancreatic Islets and Interaction with the Insulin-Signaling Pathway , 2003, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[26]  P. Hulley,et al.  Glucocorticoids induce rapid up-regulation of mitogen-activated protein kinase phosphatase-1 and dephosphorylation of extracellular signal-regulated kinase and impair proliferation in human and mouse osteoblast cell lines. , 2003, Endocrinology.

[27]  E. Herrera.  Implications of dietary fatty acids during pregnancy on placental, fetal and postnatal development--a review. , 2002, Placenta.

[28]  O. Kassel,et al.  Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP‐1 , 2001, The EMBO journal.

[29]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[30]  A. Weinhaus,et al.  Dexamethasone counteracts the effect of prolactin on islet function: implications for islet regulation in late pregnancy. , 2000, Endocrinology.

[31]  M. Kawai,et al.  Adaptation of pancreatic islet B-cells during the last third of pregnancy: regulation of B-cell function and proliferation by lactogenic hormones in rats. , 1999, European journal of endocrinology.

[32]  P. Vadiveloo,et al.  Glucocorticoids inhibit proliferation, cyclin D1 expression, and retinoblastoma protein phosphorylation, but not activity of the extracellular-regulated kinases in human cultured airway smooth muscle. , 1999, American journal of respiratory cell and molecular biology.

[33]  R. Sorenson,et al.  Adaptation of Islets of Langerhans to Pregnancy: β-Cell Growth, Enhanced Insulin Secretion and the Role of Lactogenic Hormones , 1997, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[34]  A. Nieuwenhuizen,et al.  Role of increased insulin demand in the adaptation of the endocrine pancreas to pregnancy. , 1997, Acta physiologica Scandinavica.

[35]  E. Haber,et al.  Mitogen-activated protein kinase phosphatase-1 in rat arterial smooth muscle cell proliferation. , 1996, The Journal of clinical investigation.

[36]  C. Der,et al.  The Mitogen-activated Protein Kinase Phosphatases PAC1, MKP-1, and MKP-2 Have Unique Substrate Specificities and Reduced Activity in Vivo toward the ERK2 sevenmaker Mutation (*) , 1996, The Journal of Biological Chemistry.

[37]  S. Bonner-Weir,et al.  Apoptosis contributes to the involution of beta cell mass in the post partum rat pancreas. , 1995, Endocrinology.

[38]  A. Boschero,et al.  Ionic mechanisms involved in the regulation of insulin secretion by muscarinic agonists , 1995, The Journal of Membrane Biology.

[39]  P. Lacy,et al.  Effect of homologous placental lactogens, prolactins, and growth hormones on islet B-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy. , 1993, Endocrinology.

[40]  Thompson Ea.  Glucocorticoid Inhibition of Gene Expression and Proliferation of Murine Lymphoid Cells in Vitro , 1989 .

[41]  W. Malaisse,et al.  Lactation-induced changes in calcium handling by rat pancreatic islets. , 1987, Journal of developmental physiology.

[42]  P. Ferré,et al.  Glucose Utilization Rates and Insulin Sensitivity In Vivo in Tissues of Virgin and Pregnant Rats , 1986, Diabetes.

[43]  G. Thiel,et al.  Calcium influx into MIN6 insulinoma cells induces expression of Egr-1 involving extracellular signal-regulated protein kinase and the transcription factors Elk-1 and CREB. , 2009, European journal of cell biology.

[44]  F. Escrivá,et al.  Increased IRS-2 content and activation of IGF-I pathway contribute to enhance beta-cell mass in fetuses from undernourished pregnant rats. , 2007, American journal of physiology. Endocrinology and metabolism.

[45]  Map.  MECHANISMS OF STEROID ACTION AND RESISTANCE IN INFLAMMATION MAP kinase phosphatase 1: a novel mediator of biological effects of glucocorticoids? , 2003 .