Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death

Details

Serval ID
serval:BIB_D459D3A48292
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death
Journal
Diabetes
Author(s)
Bonny  C., Oberson  A., Negri  S., Sauser  C., Schorderet  D. F.
ISSN
0012-1797 (Print)
Publication state
Published
Issued date
01/2001
Volume
50
Number
1
Pages
77-82
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Jan
Abstract
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.
Keywords
*Adaptor Proteins, Signal Transducing Amino Acid Sequence/genetics Apoptosis/drug effects Cell Death/drug effects Cell Line Cell Membrane Permeability Conserved Sequence/genetics Enzyme Inhibitors/*pharmacokinetics/*pharmacology Humans Interleukin-1/pharmacology Islets of Langerhans/*drug effects/*physiology JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases/*antagonists & inhibitors Molecular Sequence Data Nuclear Proteins/genetics Peptides/chemical synthesis/*pharmacokinetics/*pharmacology Proto-Oncogene Proteins c-fos/antagonists & inhibitors Proto-Oncogene Proteins c-jun/antagonists & inhibitors Trans-Activators/genetics
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 12:59
Last modification date
20/08/2019 15:54
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