AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase

J Mol Endocrinol. 2003 Apr;30(2):151-61. doi: 10.1677/jme.0.0300151.

Abstract

We have recently shown that conditions known to activate AMP-activated protein kinase (AMPK) in primary beta-cells can trigger their apoptosis. The present study demonstrates that this is also the case in the MIN6 beta-cell line, which was used to investigate the underlying mechanism. Sustained activation of AMPK was induced by culture with the adenosine analogue AICA-riboside or at low glucose concentrations. Both conditions induced a sequential activation of AMPK, c-Jun-N-terminal kinase (JNK) and caspase-3. The effects of AMPK on JNK activation and apoptosis were demonstrated by adenoviral expression of constitutively active AMPK, a condition which reproduced the earlier-described AMPK-dependent effects on pyruvate kinase and acetyl-coA-carboxylase. The effects of JNK activation on apoptosis were demonstrated by the observations that (i). its inhibition by dicumarol prevented caspase-3 activation and apoptosis, (ii). adenoviral expression of the JNK-interacting scaffold protein JIP-1/IB-1 increased AICA-riboside-induced JNK activation and apoptosis. In primary beta-cells, AMPK activation was also found to activate JNK, involving primarily the JNK 2 (p54) isoform. It is concluded that prolonged stimulation of AMPK can induce apoptosis of insulin-producing cells through an activation pathway that involves JNK, and subsequently, caspase-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Chloromethyl Ketones / metabolism
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / metabolism
  • Animals
  • Apoptosis / physiology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspases / metabolism
  • Cell Line
  • Dicumarol / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / metabolism
  • Glucose / metabolism
  • Insulin / metabolism*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Ribonucleosides / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Chloromethyl Ketones
  • Carrier Proteins
  • Enzyme Inhibitors
  • Insulin
  • Mapk8ip protein, mouse
  • Mapk8ip1 protein, rat
  • Multienzyme Complexes
  • Recombinant Fusion Proteins
  • Ribonucleosides
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Aminoimidazole Carboxamide
  • acadesine
  • Dicumarol
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Glucose