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Am J Physiol Gastrointest Liver Physiol 278: G805-G810, 2000;
0193-1857/00 $5.00
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Vol. 278, Issue 5, G805-G810, May 2000

Aging alters gastric mucosal responses to epidermal growth factor and transforming growth factor-alpha

Jerrold R. Turner1, Lei Liu2, Suzanne E. G. Fligiel3, Richard Jaszewski2,3, and Adhip P. N. Majumdar2,3,4,5

3 Veterans Affairs Medical Center and Departments of 2 Medicine, 1 Pathology, and 4 Biochemistry and Molecular Biology and 5 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48201

Administration of pharmacological doses of epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha ) in young rats stimulates gastric mucosal proliferation, but, in aged rats, the same treatment inhibits proliferation. This may be due to enhanced ligand-induced internalization of EGF receptor (EGFR). In support of this, we demonstrated that although a single injection of EGF (10 µg/kg) or TGF-alpha (5 µg/kg) in young (4-6 mo old) rats greatly increased membrane-associated EGFR tyrosine kinase activity, the same treatment slightly inhibited the enzyme activity in aged (24 mo old) rats. This treatment also produced a greater abundance of punctate cytoplasmic EGFR staining in gastric epithelium of aged rats, consistent with EGFR internalization. In vitro analyses demonstrated that exposure of isolated gastric mucosal cells from aged but not young rats to 100 pM TGF-alpha resulted in marked increases in intracellular EGFR tyrosine kinase activity and that induction of EGFR tyrosine kinase activity in mucosal membranes from aged rats occurred at doses 1,000-fold less than those required in young rats. Our data suggest that aging enhances sensitivity of the gastric mucosa to EGFR ligands. This may partly explain EGFR-mediated inhibition of gastric mucosal proliferation in aged rats.

epidermal growth factor receptor; epidermal growth factor receptor internalization; cell proliferation; tyrosine kinase


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