15044179

pubmed:Citation

2

cAMP has previously been shown to promote cell survival in a variety of cell types, but the downstream signaling pathway(s) of this antiapoptotic effect is unclear. Thus the role of cAMP signaling through PKA and cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs) in cAMP's antiapoptotic action was investigated in the present study. cAMP's protective effect against bile acid-, Fas ligand-, and TNF-alpha-induced apoptosis in rat hepatocytes was largely unaffected by the selective PKA inhibitor, Rp-8-(4-chlorophenylthio)-cAMP (Rp-cAMP). In contrast, a novel cAMP analog, 8-(4-chlorophenylthio)-2'-O-methyl (CPT-2-Me)-cAMP, which activated cAMP-GEFs in hepatocytes without activating PKA, protected hepatocytes against apoptosis induced by bile acids, Fas ligand, and TNF-alpha. The role of cAMP-GEF and PKA on activation of Akt, a kinase implicated in cAMP survival signaling, was investigated. Inhibition of PKA with RP-cAMP had no effect on cAMP-mediated Akt phosphorylation, whereas CPT-2-Me-cAMP, which did not activate PKA, induced phosphatidylinositol 3-kinase (PI3-kinase)-dependent activation of Akt. Pretreatment of hepatocytes with the PI3-kinase inhibitor, Ly-294002, prevented CPT-2-Me-cAMP's protective effect against bile acid and Fas ligand, but not TNF-alpha-mediated apoptosis. Glucagon, CPT-cAMP, and CPT-2-Me-cAMP all activated Rap 1, a downstream effector of cAMP-GEF. These results suggest that a PKA-independent cAMP/cAMP-GEF/Rap pathway exists in hepatocytes and that activation of cAMP-GEFs promotes Akt phosphorylation and hepatocyte survival. Thus a cAMP/cAMP-GEF/Rap/PI3-kinase/Akt signaling pathway may confer protection against bile acid- and Fas-induced apoptosis in hepatocytes.

eng

IM

MEDLINE

0193-1857

Print

NLM

G334-43

pubmed-meshheading:15044179-Animals, pubmed-meshheading:15044179-Apoptosis, pubmed-meshheading:15044179-Bile Acids and Salts, pubmed-meshheading:15044179-Cells, Cultured, pubmed-meshheading:15044179-Cyclic AMP, pubmed-meshheading:15044179-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:15044179-Cytoprotection, pubmed-meshheading:15044179-Guanine Nucleotide Exchange Factors, pubmed-meshheading:15044179-Hepatocytes, pubmed-meshheading:15044179-Male, pubmed-meshheading:15044179-Mitogen-Activated Protein Kinases, pubmed-meshheading:15044179-Phosphatidylinositol 3-Kinases, pubmed-meshheading:15044179-Protein-Serine-Threonine Kinases, pubmed-meshheading:15044179-Proto-Oncogene Proteins, pubmed-meshheading:15044179-Proto-Oncogene Proteins c-akt, pubmed-meshheading:15044179-Rats, pubmed-meshheading:15044179-Rats, Wistar, pubmed-meshheading:15044179-Thionucleotides, pubmed-meshheading:15044179-rap1 GTP-Binding Proteins

Activation of cAMP-guanine exchange factor confers PKA-independent protection from hepatocyte apoptosis.

Journal Article, Research Support, U.S. Gov't, P.H.S.