Effect of carboxypeptidase E deficiency on progastrin processing and gastrin messenger ribonucleic acid expression in mice with the fat mutation

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 (C...

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Published inEndocrinology (Philadelphia) Vol. 138; no. 5; pp. 1959 - 1963
Main Authors Udupi, V, Gomez, P, Song, L, Varlamov, O, Reed, J T, Leiter, E H, Fricker, L D, Greeley, Jr, G H
Format Journal Article
LanguageEnglish
Published United States 01.05.1997
Subjects
Animals
Carboxypeptidase H
Carboxypeptidases - deficiency
Carboxypeptidases - genetics
Colon - enzymology
Duodenum - enzymology
Gastrins - genetics
Gastrins - metabolism
Gene Expression
Mice
Mice, Obese
Protein Precursors - metabolism
RNA, Messenger - metabolism
Stomach - enzymology
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Summary: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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ISSN:0013-7227
DOI:10.1210/en.138.5.1959