Insulin activates caspase-3 by a phosphatidylinositol 3'-kinase-dependent pathway

Activation of the caspase proteases by c-Jun N-terminal kinase 1 (JNK1) has been proposed as a mechanism of apoptotic cell death. Here we report that insulin activates caspase-3 by a pathway requiring phosphatidylinositol 3'-kinase (PI3-kinase). JNK1 assays demonstrated that insulin treatment o...

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Bibliographic Details
Published in:Cellular signalling 1999-01, Vol.11 (1), p.15-23
Main Authors: Godbout, J P, Cengel, K A, Cheng, S L, Minshall, C, Kelley, K W, Freund, G G
Format: Article
Language:English
Subjects:
Apoptosis
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Caspase 3
Caspases - metabolism
Enzyme Activation
Humans
Insulin - metabolism
Insulin - pharmacology
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
Signal Transduction
Tumor Cells, Cultured
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Summary:Activation of the caspase proteases by c-Jun N-terminal kinase 1 (JNK1) has been proposed as a mechanism of apoptotic cell death. Here we report that insulin activates caspase-3 by a pathway requiring phosphatidylinositol 3'-kinase (PI3-kinase). JNK1 assays demonstrated that insulin treatment of myeloma cells induced 3-fold activation of JNK1. Inhibition of PI3-kinase with wortmannin and LY294002 blocked insulin-dependent activation of JNK1. Caspase assays demonstrated that insulin increased caspase-3 activity 3-fold and that inhibition of PI3-kinase blocked this effect. Cell death was doubled by insulin and was due to a 3-fold increase in apoptosis of cells in the G1/G0 phase of the cell cycle. Inhibition of PI3-kinase completely blocked this effect. Finally, inhibition of caspase-3 with benzyloxycarbonyl-Asp-2,6-dichlorobenzoyloxymethylketone blocked cell death due to insulin. Taken together, these findings indicate that insulin activates caspase-3 by a PI3-kinase-dependent pathway resulting in increased apoptosis and cell death.
ISSN:0898-6568
1873-3913
DOI:10.1016/S0898-6568(98)00024-2