Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death.
Stress conditions and proinflammatory cytokines activate the c-Jun NH2-terminal kinase (JNK), a member of the stress-activated group of mitogen-activated protein kinases (MAPKs). We recently demonstrated that inhibition of JNK signaling with the use of the islet-brain (IB) 1 and 2 proteins prevented interleukin (IL)-1beta-induced pancreatic beta-cell death. Bioactive cell-permeable peptide inhibitors of JNK were engineered by linking the minimal 20-amino acid inhibitory domains of the IB proteins to the 10-amino acid HIV-TAT sequence that rapidly translocates inside cells. Kinase assays indicate that the inhibitors block activation of the transcription factor c-Jun by JNK. Addition of the peptides to the insulin-secreting betaTC-3 cell line results in a marked inhibition of IL-1beta-induced c-jun and c-fos expression. The peptides protect betaTC-3 cells against apoptosis induced by IL-1beta. All-D retro-inverso peptides penetrate cells as efficiently as the L-enantiomers, decrease c-Jun activation by JNK, and remain highly stable inside cells. These latter peptides confer full protection against IL-1beta-induced apoptosis for up to 2 weeks of continual treatment with IL-1beta. These data establish these bioactive cell-permeable peptides as potent pharmacological compounds that decrease intracellular JNK signaling and confer long-term protection to pancreatic beta-cells from IL-1beta-induced apoptosis.
Bonny
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Division of Medical Genetics, Centre Hospitalier Universitaire Vaudois-University Hospital, Lausanne, Switzerland. christophe.bonny@chuv.hospvd.ch
Oberson
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Negri
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Sauser
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Schorderet
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D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002463:Cell Membrane Permeability; D017124:Conserved Sequence / Q000235:genetics; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D007375:Interleukin-1; C490666:MAPK8IP1 protein, human; D009687:Nuclear Proteins; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases