title: Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells.
abstract: Diabetes mellitus is a complex and heterogeneous disease, which has β-cell dysfunction at its core. Glucotoxicity affects pancreatic islets, causing β-cell apoptosis. However, the role of JNK/β-catenin signaling in glucotoxic β-cell apoptosis is not well understood. Recently, we identified tetraspanin-2 (TSPAN2) protein as a proapoptotic β-cell factor induced by glucose, suggesting that TSPAN2 might contribute to pancreatic β-cell glucotoxicity. To investigate the effects of glucose concentration on TSPAN2 expression and apoptosis, we used reverted immortalized RNAKT-15 human pancreatic β cells. High TSPAN2 levels up-regulated phosphorylated (p) JNK and induced apoptosis. p-JNK enhanced the phosphorylation of β-catenin and Dickkopf-1 (Dkk1). Dkk1 knockdown by small interfering (si)RNA up-regulated nuclear β-catenin, suggesting that it is a JNK/β-catenin-dependent pathway. siRNA-mediated TSPAN2 depletion in RNAKT-15 cells increased nuclear β-catenin. This decreased BCL2-associated X protein (Bax) activation, leading to marked protection against high glucose-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Thus, TSPAN2 might have induced Bax translocation and caspase-3 activation in pancreatic β cells, thereby promoting the apoptosis of RNAKT-15 cells by regulating the JNK/β-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-induced β-cell failure.-Hwang, I.-H., Park, J., Kim, J. M., Kim, S. I., Choi, J.-S., Lee, K.-B., Yun, S. H., Lee, M.-G., Park, S. J., Jang, I.-S. Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells.
authors.affiliation: Department of Physiology, Korea University College of Medicine, Seoul, Korea;
authors.forename: In-Hu
authors.initials: IH
authors.lastname: Hwang
authors.affiliation: Division of Biological Science and Technology, Yonsei University, Wonju, Korea;
authors.forename: Junsoo
authors.initials: J
authors.lastname: Park
authors.affiliation: NAR Center, Inc., Daejeon Oriental Hospital of Daejeon University, Daejeon, Korea;
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Division of Bioconvergence, Korea Basic Science Institute, Daejeon, Korea; and.
authors.forename: Seung Il
authors.initials: SI
authors.lastname: Kim
authors.affiliation: Division of Bioconvergence, Korea Basic Science Institute, Daejeon, Korea; and.
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Division of Bioconvergence, Korea Basic Science Institute, Daejeon, Korea; and.
authors.forename: Kyung-Bok
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Division of Bioconvergence, Korea Basic Science Institute, Daejeon, Korea; and.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Yun
authors.affiliation: Department of Physiology, Korea University College of Medicine, Seoul, Korea;
authors.forename: Min-Goo
authors.initials: MG
authors.lastname: Lee
authors.affiliation: Sangji University College of Korean Medicine, Wonju, Korea taorgi@hanmail.net.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Division of Bioconvergence, Korea Basic Science Institute, Daejeon, Korea; and jangiksn@kbsi.re.kr.
authors.forename: Ik-Soon
authors.initials: IS
authors.lastname: Jang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C512650:TSPAN2 protein, human; D059470:Tetraspanins; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: Bax; TSPAN2; glucose toxicity