Glycine-extended gastrin regulates HEK cell growth.
Posttranslational processing of progastrin to a carboxy terminally amidated form (G-NH(2)) is essential for its effect on gastric acid secretion and other biological effects mediated by gastrin/CCK-B receptors. The immediate biosynthetic precursor of G-NH(2), glycine-extended gastrin (G-Gly), does not stimulate gastric acid secretion at physiological concentrations but is found in high concentrations during development. G-NH(2) and G-Gly have potent growth stimulatory effects on gastrointestinal tissues, and G-NH(2) can stimulate proliferation of human kidney cells. Thus we sought to explore the actions of G-NH(2) and G-Gly on the human embryonic kidney cell line HEK 293. HEK 293 cells showed specific binding sites for (125)I-labeled Leu(15)-G17-NH(2) and (125)I-Leu(15)-G(2-17)-Gly. Both G-NH(2) and G-Gly induced a dose-dependent increase in [(3)H]thymidine incorporation, and both peptides together significantly increased [(3)H]thymidine incorporation above the level of either peptide alone. G-NH(2) and G-Gly were detected by radioimmunoassay in serum-free conditioned media. Antibodies directed against G-NH(2) and G-Gly lead to a significant reduction in [(3)H]thymidine incorporation. G-NH(2) but not G-Gly increased intracellular Ca(2+) concentration. We conclude that G-NH(2) and G-Gly act cooperatively via distinct receptors to stimulate the growth of a nongastrointestinal cell line (HEK 293) in an autocrine fashion.
Stepan
V M
VM
Department of Pediatrics, University of Michigan, Medical Center, Ann Arbor, Michigan 48109, USA.
Krametter
D F
DF
Matsushima
M
M
Todisco
A
A
Delvalle
J
J
Dickinson
C J
CJ
D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology; D005755:Gastrins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D007425:Intracellular Membranes / Q000378:metabolism; D007668:Kidney / Q000196:embryology*; D009994:Osmolar Concentration; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D018009:Receptors, Glycine / Q000378:metabolism
D005755:Gastrins; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D018009:Receptors, Glycine; C086854:glycine-extended gastrin 17; D002118:Calcium