Gastrin regulates the human histidine decarboxylase promoter through an AP-1-dependent mechanism.
The histidine decarboxylase (HDC) gene is regulated transcriptionally by gastrin and phorbol 12-myristate 13-acetate (PMA) through a protein kinase C (PKC)-related pathway. To determine the role of AP-1 (fos/jun) in the regulation of the HDC promoter, gastric cancer (AGS-B) cells stably expressing the cholecystokinin-B/ gastrin receptor and the 1.8-kb human (h) HDC-luciferase (luc) construct were cotransfected with constructs expressing c-fos and c-jun. Overexpression of c-fos and c-jun activated the HDC promoter in a dose-dependent fashion in 1.8-kb hHDC-luc/AGS-B cells as well as in transfected F9 embryonal carcinoma cells, which lack endogenous AP-1 activity. PMA was unable to activate the HDC promoter in F9 cells, which were not transfected with c-fos and c-jun. Gastrin stimulation increased c-fos and c-jun mRNA abundance and AP-1-dependent transcriptional activity, as assessed by a reporter construct in which the CAT reporter gene is under the control of a 12-O-tetradecanoylphorbol-13-acetate response element multimer. Gastrin-stimulated HDC promoter activity was blocked by transfection of c-fos antisense and dominant negative c-jun expression constructs. Finally, overexpression of c-fos and c-jun activated the hHDC promoter through a downstream cis-acting element (gastrin response element), which does not bind AP-1. In conclusion, activation of AP-1 is essential for gastrin-stimulated HDC transcription, but the mechanism appears to be indirect.
Höcker
M
M
Department of Medicine, Massachusetts General Hospital, Boston 02114, USA.
Zhang
Z
Z
Merchant
J L
JL
Wang
T C
TC
D016375:Antisense Elements (Genetics); D002461:Cell Line, Transformed; D005755:Gastrins / Q000494:pharmacology / Q000502:physiology*; D015870:Gene Expression; D016762:Genes, fos; D016758:Genes, jun; D006640:Histidine Decarboxylase / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D016375:Antisense Elements (Genetics); D005755:Gastrins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D006640:Histidine Decarboxylase