Abstract
The JNK pathway is known to be activated in several tissues in the diabetic state, and is possibly involved in the development of insulin resistance and suppression of insulin biosynthesis. Here we show a potential new therapy for diabetes using cell-permeable JNK-inhibitory peptide. Intraperitoneal administration of the peptide led to its transduction into various tissues in vivo, and this treatment markedly improved insulin resistance and ameliorated glucose tolerance in diabetic mice. These data indicate that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK-inhibitory peptide may have promise as a new therapeutic agent for diabetes.
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References
Hibi, M., Lin, A., Smeal, T., Minden, A. & Karin, M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 7, 2135–2148 (1993).
Derijard, B. et al. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76, 1025–1037 (1994).
Davis, R. Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252 (2000).
Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).
Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).
Aguirre, V., Uchiuda, T., Yenush, L., Davis, R. & White, M.F. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J. Biol. Chem. 275, 9047–9054 (2000).
Manning, A.M. & Davis, R. Targeting JNK for therapeutic benefit: from junk to gold? Nature Rev. Drug Discov. 2, 554–565 (2003).
Kaneto, H. et al. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J. Biol. Chem. 277, 30010–30018 (2002).
Kawamori, D. et al. Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH2-terminal kinase. Diabetes 52, 2896–2904 (2003).
Schwarze, S.R., Ho, A., Vocero-Akbani, A.M. & Dowdy, S.F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569–1572 (1999).
Elliott, G. & O'Hare, P. Intracellular trafficking and protein delivery by a herpesvirus structure protein. Cell 88, 223–233 (1997).
Frankel, A.D. & Pabo, C.O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55, 1189–1193 (1988).
Nagahara. H. et al. Transduction of full-length TAT fusion proteins into mammalian cells:TAT-p-27Kip1 induces cell migration. Nat. Med. 4, 1449–1452 (1998).
Rothbard, J.B. et al. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat. Med. 6, 1253–1257 (2000).
Noguchi, H., Kaneto, H., Weir, G.C. & Bonner-Weir, S. PDX-1 protein containing its own Antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells. Diabetes 52, 1732–1737 (2003).
Noguchi, H. et al. A new cell-permeable peptide allows successful allogeneic islet transplantation in mice. Nat. Med. 10, 305–309 (2004).
Bonny, C., Oberson, A., Negri, S., Sause, C. & Schorderet, D.F. Cell-permeable peptide inhibitors of JNK: novel blockers of β-cell death. Diabetes 50, 77–82 (2001).
Ichijo, H. et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38signaling pathways. Science 275, 90–94 (1997).
Tobiume, K. et al. ASK1 is required for sustained activations of JNK/p38MAP kinases and apoptosis. EMBO Rep. 2, 222–228 (2001).
Corbett, J.A., Wang, J.L., Sweetland, M.A., Lancaster, J.R. Jr. & McDaniel, M.L. Interleukin 1β induces the formation of nitric oxide by β-cells purified from rodent islets of Langerhans: evidence for the β-cell as a source and site of action of nitric oxide. J. Clin. Invest. 90, 2384–2391 (1992).
Kaneto, H. et al. Apoptotic cell death triggered by nitric oxide in pancreatic β-cells. Diabetes 44, 733–738 (1995).
Ammendrup, A. et al. The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic β-cells. Diabetes 49, 1468–1476 (2000).
Bonny, C. et al. IB1 reduces cytokine-induced apoptosis of insulin-secreting cells. J. Biol. Chem. 275, 16466–16472 (2000).
Mandrup-Poulsen, T. β-cell apoptosis: stimuli and signaling. Diabetes 50, S58–S63 (2001).
Waeber, G. et al. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat. Genet. 24, 291–295 (2000).
Acknowledgements
This work was supported in part by grants from the Ministry of Education of Japan (to Y.Y.). We thank Y. Sasaki for her technical assistance, C. Yokogawa for her secretarial assistance and H.A. Popiel for comments on the manuscript.
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Kaneto, H., Nakatani, Y., Miyatsuka, T. et al. Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat Med 10, 1128–1132 (2004). https://doi.org/10.1038/nm1111
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DOI: https://doi.org/10.1038/nm1111
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