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