Fas/APO-1(CD95)-induced apoptosis of primary hepatocytes is inhibited by cAMP.
Fas/APO-1(CD-95) activation induced rapid apoptotic cell death of primary rat hepatocytes in suspension culture. Activators of cAMP-dependent protein kinase (glucagon and N6-benzoyl-cAMP) protected against apoptosis, whereas the specific cAMP-kinase inhibitor (Rp)-8-Br-cAMPS enhanced Fas-induced death. The latter observation indicated that even the basal cAMP level may provide partial protection against Fas-induced hepatocyte apoptosis. Two-dimensional gel electrophoresis revealed decreased phosphorylation of several proteins in Fas-activated cells. Most of these dephosphorylations were attenuated or not observed in cells simultaneously stimulated by anti-Fas and cAMP, indicating a tight correlation between the dephosphorylations and death. Elevation of cAMP rescued the cells not only from the Fas-induced morphological changes and dephosphorylation, but also from functional deterioration. Whereas cells treated with anti-Fas alone quickly lost plating efficiency, hepatocytes co-treated with glucagon retained their ability to adhere and spread on a collagen substratum.
Fladmark
K E
KE
Department of Anatomy and Cell Biology, University of Bergen, Norway.
Gjertsen
B T
BT
Døskeland
S O
SO
Vintermyr
O K
OK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D008099:Liver / Q000166:cytology*; D008297:Male; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019014:fas Receptor / Q000502:physiology*
D011506:Proteins; D019014:fas Receptor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases