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Effect of Carboxypeptidase E Deficiency on Progastrin Processing and Gastrin Messenger Ribonucleic Acid Expression in Mice with the fat Mutation¹

Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77555; the Department of Molecular Pharmacology, Albert Einstein College of Medicine (L.S., O.V., L.D.F.), Bronx, New York 10461; and the Jackson Laboratory (E.H.L.), Bar Harbor, Maine 04609

Address all correspondence and requests for reprints to: George H. Greeley, Jr., Ph.D., Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0725. E-mail: ggreeley{at}mspo2.med.utmb.edu

Proforms of gastrointestinal peptides are cleaved at paired basic residues into intermediate forms. Paired basic residues at the C-terminal then are excised by carboxypeptidases before the peptide is amidated. An obese mouse, called Cpe^fat/Cpe^fat, has a missense mutation in carboxypeptidase E (CPE) with no pancreatic CPE activity and a reduced processing of pancreatic proinsulin to insulin. The purpose of this study was 1) to look for the presence of CPE in the antrum of the stomach, duodenum, and colon in the Cpe^fat/Cpe^fat mouse; 2) to determine whether CPE is involved in the processing of progastrin (Pro-G) to its carboxyl-terminal amidated form; and 3) to determine whether a decrease in amidated gastrin results in an up-regulation of stomach gastrin messenger RNA (mRNA) levels. In Cpe^fat/Cpe^fat mice, CPE activity was absent in the antrum and colon. In Cpe^fat/Cpe^fat mice, amidated gastrin levels were reduced significantly. Levels of the precursor for amidated gastrin (gastrin-Gly-Arg-Arg) were markedly elevated. Gastrin mRNA levels were increased approximately 2-fold over the levels in Cpe^fat/Cpe^fat mice. These results indicate that CPE is needed for processing progastrin to gastrin in the stomach and that amidated gastrin exerts an inhibitory feedback effect on gastrin mRNA levels.

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