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Cell-Permeable Peptide Inhibitors of JNK

Novel Blockers of ß-Cell Death

From the Division of Medical Genetics, Centre Hospitalier Universitaire Vaudois—University Hospital, 1011 Lausanne, Switzerland.

Address correspondence and reprint requests to Christophe Bonny, PhD, Division of Medical Genetics, CHUV—University Hospital, 1011 Lausanne, Switzerland. E-mail: christophe.bonny{at}chuv.hospvd.ch .

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)-1ß—induced pancreatic ß-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 ßTC-3 cell line results in a marked inhibition of IL-1ß—induced c-jun and c-fos expression. The peptides protect ßTC-3 cells against apoptosis induced by IL-1ß. 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-1ß—induced apoptosis for up to 2 weeks of continual treatment with IL-1ß. These data establish these bioactive cell-permeable peptides as potent pharmacological compounds that decrease intracellular JNK signaling and confer long-term protection to pancreatic ß-cells from IL-1ß—induced apoptosis.

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