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Am J Physiol Gastrointest Liver Physiol 286: G992-G999, 2004. First published February 5, 2004; doi:10.1152/ajpgi.00206.2002
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HORMONES AND SIGNALING

Gastrin regulates the heparin-binding epidermal-like growth factor promoter via a PKC/EGFR-dependent mechanism

Natalie F. Sinclair,1 Wandong Ai,1 Raktima Raychowdhury,2 Meixia Bi,1 Timothy C. Wang,1 Theodore J. Koh,1 and John T. McLaughlin3

1University of Massachusetts Memorial Medical Center, Division of Digestive Diseases and Nutrition, Worcester, 01605; 2Massachusetts General Hospital, Gastrointestinal Unit, Boston, Massachusetts 02114; and 3Gastrointestinal Sciences, Manchester University, Salford M6 8HD, United Kingdom

Submitted 31 May 2002 ; accepted in final form 21 January 2004

Gastrin is a known growth/differentiation factor for the gastric mucosa. Its effects are likely mediated by the induction of heparin-binding epidermal-like growth factor (HB-EGF), a member of the EGF family of growth factors that is expressed by gastric parietal cells. In this study, we investigated the regulation of the HB-EGF promoter by gastrin in a human gastric cancer cell line. Serial human HB-EGF promoter-luciferase reporter deletion constructs and heterologous promoter constructs were transfected into AGS-E cells and stimulated with gastrin (10–7 M) with or without various signal transduction inhibitors. EMSA were also performed. Gastrin stimulation resulted in a fivefold increase in HB-EGF-luciferase activity. The cis-acting element mediating gastrin responsiveness was mapped to the –69 to –58 region of the HB-EGF promoter. Gastrin stimulation was PKC dependent and at least partially mediated by activation of the EGF receptor.

peptide hormone; gastrointestinal mucosa


Address for reprint requests and other correspondence: T. C. Wang, UMass Memorial Medical Center, Division of Digestive Diseases and Nutrition, 55 Lake Ave. North, Worcester, MA 01655 (E-mail: timothy.wang{at}umassmed.edu).




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