The glucagon-like peptide-2 receptor mediates direct inhibition of cellular apoptosis via a cAMP-dependent protein kinase-independent pathway

被引:91
作者
Yusta, B [1 ]
Boushey, RP [1 ]
Drucker, DJ [1 ]
机构
[1] Univ Toronto, Toronto Gen Hosp, Banting & Best Diabet Ctr, Dept Med, Toronto, ON M5G 1L7, Canada
关键词
D O I
10.1074/jbc.M005510200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mucose 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.
引用
收藏
页码:35345 / 35352
页数:8
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