Analysis of the cellular and molecular mechanisms of trophic action of a misspliced form of the type B cholecystokinin receptor present in colon and pancreatic cancer.
Gastrin and cholecystokinin (CCK) have trophic action on cells expressing wild type A or B CCK receptors. Potential relevance to pancreatic and colonic cancers was raised by the demonstration of a misspliced type B CCK receptor that, when expressed in Balb3T3 cells, had constitutive activity to stimulate intracellular calcium. We attempted to confirm and extend this observation in CHO cells by establishing lines expressing similar densities of variant or wild type B CCK receptor. While both were capable of normal binding and agonist-induced signaling, neither expressed constitutive signaling and both had similar basal growth. Agonist stimulation of cells expressing misspliced receptor had greater increases in calcium and greater growth rates than control cells despite similar MAP kinase phosphorylation responses. Thus, this variant receptor can potentiate peptide-stimulated signaling and trophic action and may contribute to the proliferation of neoplasms expressing it.
Cheng
Zhi-Jie
ZJ
Mayo Clinic Cancer Center, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic in Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
Harikumar
Kaleeckal G
KG
Ding
Wei-Qun
WQ
Holicky
Eileen L
EL
Miller
Laurence J
LJ
D017398:Alternative Splicing; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects*; D002766:Cholecystokinin / Q000494:pharmacology; D003110:Colonic Neoplasms; D006224:Cricetinae; D003412:Cricetulus; D005755:Gastrins / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D010190:Pancreatic Neoplasms; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D043887:Receptor, Cholecystokinin B / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D005755:Gastrins; D012333:RNA, Messenger; D043887:Receptor, Cholecystokinin B; D002766:Cholecystokinin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3