title: Mitogen-activated protein kinases and protein phosphatase 5 mediate glucocorticoid-induced cytotoxicity in pancreatic islets and β-cells.
abstract: Glucocorticoid excess is associated with glucose intolerance and diabetes. In addition to inducing insulin resistance, glucocorticoids impair β-cell function and cause β-cell apoptosis. In this study we show that dexamethasone activates mitogen-activated protein kinases (MAPKs) signaling in MIN6 β-cells, as evident by enhanced phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK). In contrast, the integrated stress response pathway was inhibited by dexamethasone. A p38 MAPK inhibitor attenuated dexamethasone-induced apoptosis in β-cells and isolated islets and decreased glucocorticoid receptor phosphorylation at S220. In contrast, a JNK inhibitor augmented DNA fragmentation and dexamethasone-induced formation of cleaved caspase 3. We also show that inhibition of protein phosphatase 5 (PP5) augments apoptosis in dexamethasone-exposed islets and β-cells, with a concomitant activation of p38 MAPK. In conclusion, our data provide evidence that in islets and β-cells, p38 MAPK and JNK phosphorylation work in concert with PP5 to regulate the cytotoxic effects exerted by glucocorticoids.
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Fransson
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Victoria
authors.initials: V
authors.lastname: Rosengren
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Titu Kumar
authors.initials: TK
authors.lastname: Saha
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nina
authors.initials: N
authors.lastname: Grankvist
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tohidul
authors.initials: T
authors.lastname: Islam
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Department of Internal Medicine, Södertälje Hospital, SE 152 86 Södertälje, Sweden.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Honkanen
authors.affiliation: Department of Internal Medicine, Södertälje Hospital, SE 152 86 Södertälje, Sweden; Department of Biochemistry and Molecular Biology, University of South Alabama, College of Medicine, Mobile, AL, USA.
authors.forename: Åke
authors.initials: Å
authors.lastname: Sjöholm
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Research Unit, Södertälje Hospital, SE-152 86 Södertälje, Sweden. Electronic address: henrik.ortsater@ki.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ortsäter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013312:Stress, Physiological / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D003907:Dexamethasone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Apoptosis; Glucocorticoids; JNK; Pancreatic islet; Protein phosphatase 5; p38 MAPK