Glycine-extended gastrin regulates HEK cell growth

Abstract

Posttranslational processing of progastrin to a carboxy terminally amidated form (G-NH2) 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-NH2, glycine-extended gastrin (G-Gly), does not stimulate gastric acid secretion at physiological concentrations but is found in high concentrations during development. G-NH2 and G-Gly have potent growth stimulatory effects on gastrointestinal tissues, and G-NH2 can stimulate proliferation of human kidney cells. Thus we sought to explore the actions of G-NH2 and G-Gly on the human embryonic kidney cell line HEK 293. HEK 293 cells showed specific binding sites for 125I-labeled Leu15-G17-NH2and125I-Leu15-G2—17-Gly. Both G-NH2 and G-Gly induced a dose-dependent increase in [3H]thymidine incorporation, and both peptides together significantly increased [3H]thymidine incorporation above the level of either peptide alone. G-NH2 and G-Gly were detected by radioimmunoassay in serum-free conditioned media. Antibodies directed against G-NH2 and G-Gly lead to a significant reduction in [3H]thymidine incorporation. G-NH2 but not G-Gly increased intracellular Ca2+concentration. We conclude that G-NH2 and G-Gly act cooperatively via distinct receptors to stimulate the growth of a nongastrointestinal cell line (HEK 293) in an autocrine fashion.