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

Diabetes. 2001 Jan;50(1):77-82. doi: 10.2337/diabetes.50.1.77.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Interleukin-1 / pharmacology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / physiology*
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Peptides / chemical synthesis
  • Peptides / pharmacokinetics*
  • Peptides / pharmacology*
  • Proto-Oncogene Proteins c-fos / antagonists & inhibitors
  • Proto-Oncogene Proteins c-jun / antagonists & inhibitors
  • Trans-Activators / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Enzyme Inhibitors
  • Interleukin-1
  • MAPK8IP1 protein, human
  • Nuclear Proteins
  • Peptides
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Trans-Activators
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases