The rat histidine decarboxylase promoter is regulated by gastrin
through a protein kinase c pathway.
H[diaeresis]ocker, Michael, Zhengsheng Zhang, David A. Fenstermacher,
Sven T[angstrom]agerud, Marybeth Chulak, David Joseph, and Timothy C.
Wang.
Gastrointestinal Unit and Department of Medicine, Massachusetts
General Hospital, Boston, Massachusetts 02114, Department Pediatrics,
School of Medicine, University of North Carolina, The Curriculum in
Genetics and Molecular Biology, University of North Carolina, Chapel
Hill, North Carolina 27599
APStracts 2:0237G, 1995.
The enzyme L-histidine decarboxylase (HDC; L-histidine carboxy-lyase,
EC 4.1.1.22), which converts L-histidine to histamine, plays a key
role in the regulation of acid secretion. In the rat and human
stomach, the peptide hormone gastrin appears to be one of the main
regulators of HDC expression. In rats, marked elevation of gastric
HDC mRNA abundance was observed within 12 hours after induction of
hypergastrinemia by a single injection of the proton-pump blocker
omeprazole. In situ hybridization revealed that HDC expression
occurred in the basal third of gastric glands where enterochromaffin
-like cells are localized. In order to study the regulation of HDC
gene transcription, 1,291 nucleotides of the 5'-flanking region of
the rat HDC gene and the non-coding portion of exon 1 were cloned and
sequenced. Gastrin and CCK-8 equipotently stimulated the
transcriptional activity of the rat HDC promoter 3-4-fold, and
deletion analysis revealed the presence of a gastrin response element
within 201 nucleotides upstream of the translational start site.
Time-course studies revealed maximal activation of the HDC promoter
after 12-36 h. Direct stimulation of PKC with the phorbol ester PMA
substantially elevated rat HDC promoter activity, whereas induction
of Ca2+-dependent signaling pathways with thapsigargin was without
effect. Down-regulation or blockade of PKC abolished the effects of
gastrin and PMA on the HDC promoter. These data indicate that
stimulation of the CCK-B/gastrin receptor activates the rat HDC
promoter in a time- and dose-dependent fashion and that this effect
is primarily mediated via a PKC-dependent signaling pathway. Use of
HDC as a model gene will allow further investigation of the
intracellular pathways that are involved in gastrin-dependent gene
regulation.
Received 15 August 1995; accepted in final form 20 October 1995.
APS Manuscript Number G356-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 November 95