M. Hocker et al., RAT HISTIDINE-DECARBOXYLASE PROMOTER IS REGULATED BY GASTRIN THROUGH A PROTEIN-KINASE-C PATHWAY, American journal of physiology: Gastrointestinal and liver physiology, 33(4), 1996, pp. 619-633
The enzyme L-histidine decarboxylase (HDC; EC 4.1.1.22), which convert
s 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, m
arked elevation of gastric HDC mRNA abundance was observed within 12 h
after induction of hypergastrinemia by a single injection of the prot
on-pump blocker omeprazole. In situ hybridization revealed that HDC ex
pression occurred in the basal third of gastric glands where enterochr
omaffin-like cells are localized. To study the regulation of HDC gene
transcription, 1,291 nucleotides of the 5'-flanking region of the rat
HDC gene and the noncoding portion of exon 1 were cloned and sequenced
. Gastrin and cholecystokinin (CCK) octapeptide equipotently stimulate
d the transcriptional activity of the rat HDC promoter three- to fourf
old, and deletion analysis revealed the presence of a gastrin response
element within 201 nucleotides upstream of the translational start si
te. Time-course studies revealed maximal activation of the HDC promote
r after 12-36 h. Direct stimulation of protein kinase C (PKC) with the
phorbol ester phorbol 12-myristate 13-acetate (PMA) substantially ele
vated rat HDC promoter activity, whereas induction of Ca2+-dependent s
ignaling pathways with thapsigargin was without effect. Downregulation
or blockade of PKC abolished the effects of gastrin and PMA on the HD
C 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 inve
stigation of the intracellular pathways that are involved in gastrin-d
ependent gene regulation.