Gastrin-induced DNA synthesis requires p38-MAPK activation via PKC/Ca(2+) and Src-dependent mechanisms.
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.
Dehez
S
S
Groupe de Recherche de Biologie et Pathologie Digestives, INSERM U.531, CHU Rangueil, 1 avenue J. Poulhes, Institut Louis Bugnard, Bat. L3, 31403 Toulouse, France.
Daulhac
L
L
Kowalski-Chauvel
A
A
Fourmy
D
D
Pradayrol
L
L
Seva
C
C
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005755:Gastrins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin; D014162:Transfection; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D005755:Gastrins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019284:Thapsigargin; D004247:DNA; D019061:src-Family Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D002118:Calcium; D000077191:Wortmannin