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 immortalizedRNAKT-15 human pancreatic β cells.High TSPAN2 levels up-regulated phosphorylated (p) JNK and induced apoptosis. p-JNK enhanced the phosphorylation of b-catenin and Dickkopf-1 (Dkk1). Dkk1 knockdownbysmall interfering (si)RNAup-regulated nuclearb-catenin, suggestingthat it isaJNK/β-catenin-dependent pathway. siRNA-mediatedTSPAN2depletion inRNAKT-15 cells increased nuclearb-catenin.ThisdecreasedBCL2- associated X protein (Bax) activation, leading to marked protection against high glucose-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Thus, TSPAN2might have induced Bax translocation and caspase-3 activation in pancreatic β cells, thereby promoting the apoptosis ofRNAKT-15 cells by regulating the JNK/ b-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-inducedβ-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.
Bibliographical noteFunding Information:
This work was supported by the Basic Science Research Programthrough the National Research Foundation of Korea (NRF), funded by Ministry of Education Grants 2015R1D1A1A01058744 and 2014R1A1A2058114, and supported by Korea Basic Science Institute Grant D36403.
All Science Journal Classification (ASJC) codes
- Molecular Biology