Gastrin and Glycine-extended Progastrin Processing Intermediates Induce Different Programs of Early Gene Activation

Y. Takeuchi
1995 Journal of Biological Chemistry  
We recently reported that gastrin and glycine-extended progastrin processing intermediates (G-Gly) exert growth-promoting effects on AR4 -2J cells (derived from rat pancreas) via interaction with distinct receptors. In this study we sought to investigate the mechanisms by which gastrin and G-Gly stimulate cell proliferation. While gastrin increased [Ca 2؉ ] i in AR4 -2J cells, G-Gly had no effect. Similarly, G-Gly had no effect either on basal and 10 ؊7 M vasoactive intestinal
more » ... ted cAMP generation, although gastrin is known to inhibit cAMP generation. Gastrin dose dependently stimulated AR4 -2J cell mRNA content of both c-fos and c-jun, two genes known to function in regulating cell proliferation, but G-Gly had no effect. Gastrin also induced the expression of luciferase in AR4 -2J cells transfected with a construct consisting of a luciferase reporter gene coupled to the serum response element of the c-fos gene promoter. In similar fashion, gastrin stimulated the activity of mitogen-activated protein kinase, an enzyme known to mediate the induction of the c-fos serum response element in response to growth factor stimulation. Although G-Gly had none of these effects of gastrin in AR4 -2J cells, it stimulated activity of c-Jun amino-terminal kinase, an enzyme known to phosphorylate and transcriptionally activate c-Jun. These data support the notion that gastrin stimulates cell proliferation by inducing c-fos and c-jun gene expression, while G-Gly acts by post-translationally regulating early gene transcriptional activation. Our studies represent a novel model in which both the precursor and the product of a key processing reaction, peptide ␣-amidation, act cooperatively to stimulate cell proliferation via distinct receptors linked to different signal transduction pathways.
doi:10.1074/jbc.270.47.28337 pmid:7499334 fatcat:i3hvbkjf2bbqdoqvrtbelaee3m