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J. Biol. Chem., Vol. 275, Issue 45, 35345-35352, November 10, 2000
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From the Department of Medicine, Banting and Best Diabetes Centre,
Toronto General Hospital, University of Toronto,
Toronto, Ontario M5G 2C4, Canada
Glucagon and the glucagon-like peptides regulate
metabolic functions via signaling through a glucagon receptor subfamily
of G protein-coupled receptors. Activation of glucagon-like
peptide-2 receptor (GLP-2R) signaling maintains the integrity of the
intestinal epithelial mucosa via regulation of crypt cell
proliferation. Because GLP-2 decreases mortality and reduces intestinal
apoptosis in rodents after experimental injury, we examined whether
GLP-2R signaling directly modifies the cellular response to external injury. We show here that activation of GLP-2R signaling inhibits cycloheximide-induced apoptosis in baby hamster kidney fibroblasts expressing a transfected GLP-2 receptor. GLP-2 reduced DNA
fragmentation and improved cell survival, in association with reduced
activation of caspase-3 and decreased poly(ADP-ribose) polymerase
cleavage and reduced caspase-8 and caspase-9-like activities. Both
GLP-2 and forskolin reduced mitochondrial cytochrome c
release and decreased the cycloheximide-induced cleavage of caspase-3
in the presence or absence of the PKA inhibitor H-89. Similarly, GLP-2
increased cell survival following cycloheximide in the presence of the
kinase inhibitors PD98054 and LY294002. These findings provide evidence that signaling through G protein-coupled receptors of the glucagon superfamily is directly linked to regulation of apoptosis and suggest
the existence of a cAMP-dependent protein kinase-,
phosphatidylinositol 3-kinase-, and mitogen-activated protein
kinase-independent pathway coupling GLP-2R signaling to caspase
inhibition and cell survival.
The Glucagon-like Peptide-2 Receptor Mediates Direct
Inhibition of Cellular Apoptosis via a
cAMP-dependent Protein Kinase-independent
Pathway*
, and
*
This work was supported in part by grants from the Medical
Research Council of Canada and the Ontario Research and Development Challenge Fund.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Research fellow of the Medical Research Council of Canada.
§
Senior Scientist of the Medical Research Council of Canada.
Consultant to NPS Pharmaceuticals Corp. To whom correspondence should be addressed: Toronto General Hospital, 101 College St., CCRW3-838, Toronto, ON M5G 2C4, Canada. Tel.: 416-340-4125; Fax: 416-978-4108; E-mail: d.drucker@utoronto.ca.
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