Gastrin (G17) has a CCK_B receptor-mediated growth-promoting effect on the AR42J rat acinar cell line that is linked to induction of both mitogen-activated protein kinase (MAPK) and c-fos gene expression. We investigated the mechanisms that regulate the growth factor action of G17 on the rat pituitary adenoma cell line GH₃. Both AR42J and GH₃ cells displayed equal levels of CCK_B receptor expression and similar binding kinetics of ¹²⁵I-labeled G17. G17 stimulation of cell proliferation was identical in both cell lines. G17 stimulation of GH₃ cell proliferation was completely blocked by the CCK_B receptor antagonist D2 but not by the MEK inhibitor PD-98059 or the protein kinase C inhibitor GF-109203X, which completely inhibited G17 induction of AR42J cell proliferation. G17 induced a c-fos SRE-luciferase reporter gene plasmid more than fourfold in the AR42J cells, whereas it had no effect in the GH₃ cells. In contrast to what we observed in the AR42J cells, G17 failed to stimulate MAPK activation and Shc tyrosyl phosphorylation and association with the adapter protein Grb2. Epidermal growth factor induced the MAPK pathway in the GH₃ cells, demonstrating the integrity of this signaling system. G17 induced Ca²⁺ mobilization in both the GH₃ and AR42J cells. The calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide inhibited AR42J cell proliferation by 20%, whereas it completely blocked G17 induction of GH₃ cell growth. The Ca²⁺ ionophore ionomycin stimulated GH₃ cell proliferation to a level similar to that observed in response to G17, but it had no effect on AR42J cell proliferation. Thus there are cell type specific differences in the requirement of the MAPK pathway for the growth factor action of G17. Whereas in the AR42J cells G17 stimulates cell growth through activation of MAPK and c-fos gene expression, in the GH₃ cells, G17 fails to activate MAPK, and it induces cell proliferation through Ca²⁺-dependent signaling pathways. Furthermore, induction of Ca²⁺ mobilization in the AR42J cells appears not to be sufficient to sustain cell proliferation.

cellular proliferation; early response genes; protein kinases; transcriptional regulation; c-fos; mitogen-activated protein kinases; extracellular signal-regulated protein kinases

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