title: JNK1 Deficient Insulin-Producing Cells Are Protected against Interleukin-1β-Induced Apoptosis Associated with Abrogated Myc Expression.
abstract: The relative contributions of the JNK subtypes in inflammatory β-cell failure and apoptosis are unclear. The JNK protein family consists of JNK1, JNK2, and JNK3 subtypes, encompassing many different isoforms. INS-1 cells express JNK1α1, JNK1α2, JNK1β1, JNK1β2, JNK2α1, JNK2α2, JNK3α1, and JNK3α2 mRNA isoform transcripts translating into 46 and 54 kDa isoform JNK proteins. Utilizing Lentiviral mediated expression of shRNAs against JNK1, JNK2, or JNK3 in insulin-producing INS-1 cells, we investigated the role of individual JNK subtypes in IL-1β-induced β-cell apoptosis. JNK1 knockdown prevented IL-1β-induced INS-1 cell apoptosis associated with decreased 46 kDa isoform JNK protein phosphorylation and attenuated Myc expression. Transient knockdown of Myc also prevented IL-1β-induced apoptosis as well as caspase 3 cleavage. JNK2 shRNA potentiated IL-1β-induced apoptosis and caspase 3 cleavage, whereas JNK3 shRNA did not affect IL-1β-induced β-cell death compared to nonsense shRNA expressing INS-1 cells. In conclusion, JNK1 mediates INS-1 cell death associated with increased Myc expression. These findings underline the importance of differentiated targeting of JNK subtypes in the development of inflammatory β-cell failure and destruction.
authors.affiliation: Immuno-Endocrinology Lab, Endocrinology Research Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark; Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Michala
authors.initials: M
authors.lastname: Prause
authors.affiliation: Hagedorn Research Institute, Novo Nordisk, 2760 Måløv, Denmark.
authors.forename: Christopher Michael
authors.initials: CM
authors.lastname: Mayer
authors.affiliation: Copenhagen Diabetes Research Center, Herlev University Hospital, 2730 Herlev, Denmark.
authors.forename: Caroline
authors.initials: C
authors.lastname: Brorsson
authors.affiliation: Biopharmaceuticals Research Unit, Novo Nordisk, 2760 Måløv, Denmark.
authors.forename: Klaus Stensgaard
authors.initials: KS
authors.lastname: Frederiksen
authors.affiliation: Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Nils
authors.initials: N
authors.lastname: Billestrup
authors.affiliation: Copenhagen Diabetes Research Center, Herlev University Hospital, 2730 Herlev, Denmark.
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.affiliation: Immuno-Endocrinology Lab, Endocrinology Research Section, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark; Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology*; D051379:Mice; D048057:Mitogen-Activated Protein Kinase 10 / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: C587672:IL1B protein, mouse; D007328:Insulin; D053583:Interleukin-1beta; D016271:Proto-Oncogene Proteins c-myc; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; C505410:Casp3 protein, rat; D053148:Caspase 3