Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells

In Hu Hwang, Junsoo Park, Jung Min Kim, Seung Il Kim, Jong Soon Choi, Kyung Bok Lee, Sung Ho Yun, Min Goo Lee, Soo Jung Park, Ik Soon Jang

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)3107-3116
Number of pages10
JournalFASEB Journal
Volume30
Issue number9
DOIs
Publication statusPublished - 2016 Sep

Fingerprint

Catenins
MAP Kinase Signaling System
Apoptosis
Glucose
bcl-2-Associated X Protein
Caspase 3
Islets of Langerhans
Chemical activation
Phosphorylation
Medical problems
Small Interfering RNA
Toxicity
Proteins
Diabetes Mellitus

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Hwang, In Hu ; Park, Junsoo ; Kim, Jung Min ; Il Kim, Seung ; Choi, Jong Soon ; Lee, Kyung Bok ; Yun, Sung Ho ; Lee, Min Goo ; Park, Soo Jung ; Jang, Ik Soon. / Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells. In: FASEB Journal. 2016 ; Vol. 30, No. 9. pp. 3107-3116.
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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 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.",
author = "Hwang, {In Hu} and Junsoo Park and Kim, {Jung Min} and {Il Kim}, Seung and Choi, {Jong Soon} and Lee, {Kyung Bok} and Yun, {Sung Ho} and Lee, {Min Goo} and Park, {Soo Jung} and Jang, {Ik Soon}",
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Hwang, IH, Park, J, Kim, JM, Il Kim, S, Choi, JS, Lee, KB, Yun, SH, Lee, MG, Park, SJ & Jang, IS 2016, 'Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells', FASEB Journal, vol. 30, no. 9, pp. 3107-3116. https://doi.org/10.1096/fj.201600240RR

Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells. / Hwang, In Hu; Park, Junsoo; Kim, Jung Min; Il Kim, Seung; Choi, Jong Soon; Lee, Kyung Bok; Yun, Sung Ho; Lee, Min Goo; Park, Soo Jung; Jang, Ik Soon.

In: FASEB Journal, Vol. 30, No. 9, 09.2016, p. 3107-3116.

Research output: Contribution to journalArticle

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T1 - Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/β-catenin signaling pathway in human pancreatic β cells

AU - Hwang, In Hu

AU - Park, Junsoo

AU - Kim, Jung Min

AU - Il Kim, Seung

AU - Choi, Jong Soon

AU - Lee, Kyung Bok

AU - Yun, Sung Ho

AU - Lee, Min Goo

AU - Park, Soo Jung

AU - Jang, Ik Soon

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N2 - 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.

AB - 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.

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