Gastrin regulates the heparin-binding epidermal-like growth factor promoter via a PKC/EGFR-dependent mechanism.
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.
Sinclair
Natalie F
NF
University of Massachusetts Memorial Medical Center, Division of Digestive Diseases and Nutrition, Worcester, 01655, USA.
Ai
Wandong
W
Raychowdhury
Raktima
R
Bi
Meixia
M
Wang
Timothy C
TC
Koh
Theodore J
TJ
McLaughlin
John T
JT
D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology*; D005755:Gastrins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D020218:Response Elements / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000502:physiology; D013237:Stereoisomerism; D014157:Transcription Factors / Q000378:metabolism; D014466:Ultraviolet Rays; D015032:Zinc / Q000378:metabolism
D005755:Gastrins; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011493:Protein Kinase C; D015032:Zinc