Gastrin-induced DNA synthesis requires p38-MAPK activation via PKC/Ca(2+) and Src-dependent mechanisms

• Published in: FEBS letters Vol. 496; no. 1; pp. 25 - 30
• Main Authors: Dehez, S, Daulhac, L, Kowalski-Chauvel, A, Fourmy, D, Pradayrol, L, Seva, C
• Format: Journal Article
• Language: English
• Published: England 04-05-2001
• Subjects: Androstadienes - pharmacology; Animals; Calcium - metabolism; CHO Cells; Chromones - pharmacology; Cricetinae; DNA - biosynthesis; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Gastrins - metabolism; Gastrins - pharmacology; GTP-Binding Proteins - metabolism; Humans; Intracellular Fluid - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Morpholines - pharmacology; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation - drug effects; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - genetics; Receptors, Cholecystokinin - metabolism; Signal Transduction - drug effects; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Thapsigargin; Transfection; Wortmannin
• ISSN: 0014-5793
• DOI: 10.1016/S0014-5793(01)02396-1

We present evidence that gastrin, binding to a G protein-coupled receptor, activates the p38-mitogen-activated protein kinase (MAPK) pathway. Blockage of protein kinase C (PKC) by GF109203X, depletion of intracellular calcium by thapsigargin or inhibition of Src family kinases by PP2 prevented p38-MAPK activation and the Src kinase activity stimulated by gastrin. Inhibition of the PI 3-kinase by wortmannin or LY294002 did not affect these responses. In addition, the p38-MAPK inhibitor, SB203580, repressed gastrin-induced [(3)H]thymidine incorporation, indicating a major role of p38-MAPK in the growth-promoting effect of gastrin. Our results demonstrate that gastrin-induced DNA synthesis requires p38-MAPK activation through mechanisms that involve calcium mobilization, PKC and Src family kinases.