Histidine Decarboxylase Promoter Research Articles

Histamine deficiency promotes accumulation of immunosuppressive immature myeloid cells and growth of murine gliomas

To elucidate mechanisms underlying epidemiological findings of decreased risk of glioma development in patients with allergies and asthma, gliomas were induced in mice deficient for histidine decarboxylase (HDC), the enzyme responsible for histamine production. These mice exhibited shortened survival and enhanced tumor growth compared to wild-type (WT) mice. Previous studies have shown a pivotal role of HDC in maturation of bone marrow (BM)-derived myeloid cells. In our glioma models, brain-infiltrating leukocytes (BIL) demonstrated an increased frequency of CD11b+Gr1+ immature myeloid cells (IMC; both CD11b+Ly6G+ and CD11b+Ly6C+ subpopulations) as well as diminished CD8+ T cell infiltration and their effector functions in HDC−/− mice compared with WT mice. Furthermore, HDC−/− IMC demonstrated a more profound immune suppression of CD8+ T cell proliferation and functions associated with increased prostaglandin E2 (PGE2) expression levels. Celecoxib, a cyclooxygenase-2 inhibitor, which is vital for PGE2 production, abrogated suppressive capabilities of HDC−/− IMC. In addition, glioma-bearing HDC-eGFP mice, in which HDC promoter drives green fluorescence protein (GFP) expression, exhibited decreased HDC promoter activities in CD11b+Gr1+ cells in the BM, spleen, and intracranial tumor site compared with non-tumor bearing HDC-eGFP mice. Additionally, in vitro culture with glioma supernatants decreased GFP expression in CD11b+Gr1+, CD11b+Ly6G+, and CD11b+Ly6C+ IMC. HDC expression levels inversely correlated with suppressive functions of CD11b+Gr1+ IMC, as GFP−CD11b+Gr1+ more profoundly inhibited CD8+ T cell proliferation compared with CD11b+Gr1+GFP+ cells. Taken together, these data show a significant role of HDC in the glioma microenvironment via maturation of myeloid cells and resulting activation of CD8+ T cells.

Histamine deficiency exacerbates myocardial injury in acute myocardial infarction through impaired macrophage infiltration and increased cardiomyocyte apoptosis

Histamine is a biogenic amine that is widely distributed and has multiple functions, but the role it plays in acute myocardial infarction (AMI) remains unclear. In this study, we investigated the origin and contribution of endogenous histamine to AMI. Histidine decarboxylase (HDC) is the unique enzyme responsible for histamine generation. Using HDC-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the HDC promoter, we identified HDC expression primarily in CD11b+Gr-1+ immature myeloid cells (IMCs) that markedly increase in the early stages of AMI. Deficiency of histamine in HDC knockout mice (HDC−/−) reduced cardiac function and exacerbated the injury of infarcted heart. Furthermore, administering either an H1 receptor antagonist (pyrilamine) or an H2 receptor antagonist (cimetidine) demonstrated a protective effect of histamine against myocardial injury. The results of in vivo and in vitro assays showed that histamine deficiency promotes the apoptosis of cardiomyocytes and inhibits macrophage infiltration. In conclusion, CD11b+Gr-1+ IMCs are the predominant HDC-expressing sites in AMI, and histamine plays a protective role in the process of AMI through inhibition of cardiomyocyte apoptosis and facilitation of macrophage infiltration.

Activation of hypoxia-inducible factor-1 regulates human histidine decarboxylase expression.

Histidine decarboxylase (HDC) catalyzes the formation of histamine from histidine. Histamine has various effects in physiological and pathological reactions, such as inflammation, cell growth, and neuro-transmission. We investigated the role of hypoxia-inducible factor (HIF)-1 on hypoxia-induced HDC expression in human mast cell line, HMC-1 cells and mouse bone marrow-derived mast cells (BMMCs). Hypoxia significantly increased histamine production. HDC expression and activity were induced by hypoxia. Additionally, when cells were transfected with a native form of HIF-1alpha, hypoxia could induce higher HDC expression than in the nontransfected cell. HIF-1 binding activity for HDC 5' flanking region (HFR) was similar to that for the hypoxia-responsive element. Using HDC promoter deletion analysis, we also demonstrated that HFR was regulated by HIF-1 activation. In addition, depletion of HIF-1alpha prevents hypoxic induction of HDC in BMMCs. In conclusion, these results demonstrate that hypoxia induces HDC expression by transcriptional mechanisms dependent upon HIF-1.

Induction of histidine decarboxylase in macrophages inhibited by the novel NF-κB inhibitor (−)-DHMEQ

Histamine often causes inflammation, and this amine is produced by histidine decarboxylase (HDC). We found that (−)-DHMEQ, an NF-κB inhibitor, inhibited lipopolysaccharide (LPS)-induced histamine production and HDC induction in mouse macrophage cell line RAW264.7. However, as there is no κB site in the HDC promoter, we studied the mechanism of inhibition. Knockdown of the transcription factor C/EBPβ reduced the HDC expression in LPS-treated cells. (−)-DHMEQ inhibited the C/EBPβ transcriptional activity in a reporter assay and in an electrophoresis mobility shift assay. But it did not inhibit the in vitro binding of C/EBPβ to DNA. It also did not lower the nuclear amount of C/EBPβ. On the other hand, the addition of recombinant p65, a component of NF-κB, enhanced the activity of C/EBPβ acting as a cofactor in vitro. Then, we found that (−)-DHMEQ lowered the nuclear amount of p65. Thus, inhibition of the C/EBPβ activity by (−)-DHMEQ would be due to a reduction in the amount of nuclear p65, which has a co-activator activity for C/EBPβ that is essential for the HDC induction. (−)-DHMEQ may be useful as an anti-inflammatory agent by lowering the histamine production in the body.

Yin yang 1 (YY1) represseshistidine decarboxylasegene expression with SREBP-1a in part through an upstream Sp1 site

Histidine decarboxylase (HDC) is the enzyme that converts histidine to histamine, a bioamine that plays an important role in many physiological aspects including allergic responses, inflammation, neurotransmission, and gastric acid secretion. In previous studies, we demonstrated that Kruppel-like factor 4 represses HDC promoter activity in a gastric cell line through both an upstream Sp1-binding GC box (GGGCGG sequence) and downstream gastrin-responsive elements. In the current study, Yin Yang 1 (YY1), a pleiotropic transcriptional factor, was also shown in cotransfection assays to repress HDC promoter activity through the upstream GC box. DNA affinity purification assay demonstrated that YY1 was pulled down specifically by the upstream GC box. In addition, sterol-responsive element-binding protein 1a (SREBP-1a), a transcriptional factor that binds YY1, represses the HDC promoter. Interestingly, deletion analysis and cotransfection assays indicated that mutation of the upstream GC box or truncation of downstream gastrin-responsive elements in the HDC promoter disrupted the inhibitory effect of YY1 and SREBP-1a in an identical fashion. Furthermore, quantitative real-time PCR analysis indicated that gastrin treatment downregulated SREBP-1a gene expression and reduced the DNA binding activity of SREBP in EMSAs. Taken together, these results suggest that YY1 and SREBP-1a form a complex to inhibit HDC gene expression through both the upstream GC box and downstream gastrin-responsive elements and gastrin-induced activation of HDC gene expression is mediated at least partly through downregulation of transcriptional repressors such as SREBPs.

Kruppel-like Factor 4 (KLF4) Represses Histidine Decarboxylase Gene Expression through an Upstream Sp1 Site and Downstream Gastrin Responsive Elements

Histidine decarboxylase (HDC) is the enzyme that catalyzes the conversion of histidine to histamine, a bioamine that plays an important role in allergic responses, inflammation, neurotransmission, and gastric acid secretion. Previously, we demonstrated that gastrin activates HDC promoter activity in a gastric cancer (AGS-E) cell line through three overlapping downstream promoter elements. In the current study, we used the yeast one-hybrid strategy to identify nuclear factors that bind to these three elements. Among eight positives from the one-hybrid screen, we identified Kruppel-like factor 4 (KLF4) (previously known as gut-enriched Kruppel-like factor (GKLF)) as one factor that binds to the gastrin responsive elements in the HDC promoter. Electrophoretic mobility shift assays confirmed that KLF4 is able to bind all three gastrin responsive elements. In addition, transient cotransfection experiments showed that overexpression of KLF4 dose dependently and specifically inhibited HDC promoter activity. Regulation of HDC transcription by KLF4 was confirmed by changes in the endogenous HDC messenger RNA by KLF4 small interfering RNA and KLF4 overexpression. We further showed that KLF4 inhibits HDC promoter activity by competing with Sp1 at the upstream GC box and also independently by binding the three downstream gastrin responsive elements. Taken together, these results indicate that KLF4 can act to repress HDC gene expression by Sp1-dependent and -independent mechanisms.

PACAP and gastrin regulate the histidine decarboxylase promoter via distinct mechanisms.

The enterochromaffin-like (ECL) cell controls gastric acid secretion via histamine, generated by l-histidine decarboxylase (HDC). HDC expression is regulated by gastrin. However, gastrin is not alone in controlling ECL cell function. For example, the neural peptide pituitary adenylate cyclase-activating polypeptide (PACAP) also increases ECL cell proliferation. To investigate a potential role of PACAP in regulating HDC expression, we generated a series of HDC promoter-luciferase reporter constructs and transiently transfected them into PC12 cells (stably expressing the gastrin-CCK-2 receptor). We found that PACAP regulates HDC promoter activity. This is temporally biphasic, involving both adenyl cyclase and phospholipase C-dependent pathways. Deletional analysis, block mutation, and EMSA demonstrated a PACAP-response element at -177 to -170, wholly necessary for the effects of PACAP and discrete from known gastrin-responsive elements. Discrete neural and endocrine pathways regulate ECL cells through different patterns of postreceptor signaling and promoter activation, which may be appropriate to their functions in vivo.

Synergistic regulation of histidine decarboxylase promoter activity by GKLF and Sp1 through both upstream and downstream promoter elements

Synergistic regulation of histidine decarboxylase promoter activity by GKLF and Sp1 through both upstream and downstream promoter elements

B-Raf/Rap1 signaling, but not c-Raf-1/Ras, induces the histidine decarboxylase promoter in Helicobacter pylori infection.

Histidine decarboxylase (HDC) is the key enzyme for gastric histamine synthesis, and enhanced HDC expression is critically involved in the pathogenesis of gastric disorders, including gastroduodenal ulcer disease. We characterized the pathogenicity mechanism underlying activation of the HDC promoter in H. pylori-infected gastric epithelial cells and performed a detailed analysis of the participating signaling elements. We found that H. pylori infection of gastric epithelial cells activated the MEK1-2/ERK1-2 cascade through cAMP-dependent stimulation of Rap1 and B-Raf, but not Ras/c-Raf-1, leading to potent transactivation of the human HDC promoter. H. pylori-triggered elevation of adenylate cyclase activity was directed by GalphaS-subunits of heterotrimeric G proteins. Stimulation of this signaling cascade was triggered independent of bacterial-cell contact by a small molecular- weight component(s) (approximately 1 kDa) released by H. pylori and did not require a functional type IV secretion system. Thus, our studies demonstrate for the first time to our knowledge that the GalphaS-->cAMP-->Rap1--->B-Raf-->MEK1/2-->ERK1/2 pathway is critical for H. pylori-dependent epithelial gene regulation, which can be induced via a bioactive component(s) apart from the site of bacterial colonization. These results further elucidate the molecular mechanisms underlying interaction of H. pylori with gastric epithelial cells and help to define potential molecular targets for therapeutic interventions in the context of H. pylori-related gastric diseases.

Heucobacter pylori activates the human histidine decarboxylase promoter through mapk-ERK signaling pathways independent of cagA-pathogenicity island-encoded virulence factors

Heucobacter pylori activates the human histidine decarboxylase promoter through mapk-ERK signaling pathways independent of cagA-pathogenicity island-encoded virulence factors

Helicobacter pylori Activates the Histidine Decarboxylase Promoter through a Mitogen-activated Protein Kinase Pathway Independent of Pathogenicity Island-encoded Virulence Factors

Helicobacter pylori infection of the gastric mucosa is accompanied by an activated histamine metabolism. Histamine plays a central role in the regulation of gastric acid secretion and is involved in the pathogenesis of gastroduodenal ulcerations. Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine production, and its activity is regulated through transcriptional mechanisms. The present study investigated the effect of H. pylori infection on the transcriptional activity of the human HDC (hHDC) promoter in a gastric epithelial cell line (AGS) and analyzed the underlying molecular mechanisms. Our studies demonstrate that H. pylori infection potently transactivated the hHDC promoter. The H. pylori-responsive element of the hHDC gene was mapped to the sequence +1 to +27 base pairs, which shows no homology to known cis-acting elements and also functions as a gastrin-responsive element. H. pylori regulates the activity of this element via a Raf-1/MEK/ERK pathway, which was activated in a Ras-independent manner. Furthermore, we found that H. pylori-induced transactivation of the hHDC promoter was independent of the cag pathogenicity island and the vacuolating cytotoxin A gene and therefore may be exerted through (a) new virulence factor(s). A better understanding of H. pylori-directed hHDC transcription can provide novel insights into the molecular mechanisms of H. pylori-dependent gene regulation in gastric epithelial cells and may lead to new therapeutic approaches.

Oxidative Stress Activates the Human Histidine Decarboxylase Promoter in AGS Gastric Cancer Cells

Oxidant stress is thought to play a role in the pathogenesis of many gastric disorders. We have recently reported that histidine decarboxylase (HDC) promoter activity is stimulated by gastrin through a protein kinase C- and extracellular signal-regulating kinase (ERK)-dependent pathway in gastric cancer (AGS-B) cells, and this transcriptional response is mediated by a downstream cis-acting element, the gastrin response element (GAS-RE). To study the mechanism through which oxidant stress affects gastric cells, we examined the effects of hydrogen peroxide (H2O2) on HDC promoter activity and intracellular signaling in AGS-B cells. H2O2 (10 mM) specifically activated the HDC promoter 10-12-fold, and this activation was blocked by both mannitol and N-acetylcysteine. Hydrogen peroxide treatment of AGS-B cells increased the phosphorylation and kinase activity of ERK-1 and ERK-2, but did not affect Jun kinase tyrosine phosphorylation or kinase activity. In addition, treatment of AGS-B cells with H2O2 resulted in increased c-fos/c-jun mRNA expression and AP-1 activity, and also led to increased phosphorylation of epidermal growth factor receptor (EGFR) and Shc. H2O2-dependent stimulation of HDC promoter activity was completely inhibited by kinase-deficient ERKs, dominant-negative (N17 and N15) Ras, and dominant-negative Raf, and partially blocked by a dominant-negative EGFR mutant. In contrast, protein kinase C blockade did not inhibit H2O2-dependent induction of the HDC promoter. Finally, deletion analysis demonstrated that the H2O2 response element could be mapped to the GAS-RE (nucleotides 2 to 24) of the basal HDC promoter. Overall, these studies suggest that oxidant stress activates the HDC promoter through the GAS-RE, and through an Ras-, Raf-, and ERK-dependent pathway at least partially involving the EGFR.

Somatostatin type 2 receptor (SSTR2) inhibition of histidine decarboxylase (HDC) transcription is not mediated through a phosphatase pathway in the human gastric cancer cell line AGS-B

Background: Somatostatin (SS) inhibits both basal and gastrin stimulated histamine release from ECL cells in gastric mucosa. This is mediated through the SSTR2 receptor in human and rat antral mucosal strips. Histidine decarboxylase (HDC) is the enzyme responsible for histamine production in ECL cells and has previously been shown to be transcriptionally regulated through a gastrin response element. We postulated that SS may regulate the HDC promoter. The mechanisms through which SS may alter HDC transcription have not been elucidated. Methods: AGS-B cells were transfected with a plasmid containing 1.8 kb of the 5' promoter region of hHDC upsteam of the firefly luciferase reporter (1.8 kb hHDC-luc). Plasmids containing the cDNA of either human or rat SSTR2 were co-transfected. The cells were stimulated with 10 -7 M of gastrin, phothol ester (PMA) and dose responses with SS or octreotide were done. In addition overexpression of phosphatase SHP-1 and the G protein subunits Gictl and Gict3 were done using plasmids with the respective cDNA. Results.: Overexpression of both human and rat SSTR2 resulted in a dose dependent inhibition of hHDC transcription as measured by a luminometer. Maximal inhibition caused a 80% reduction in HDC transcription. This was seen in basal conditions, as well as with gastrin and PMA stimulated cells. Co-transfection with SHP-1 or its mutant did not block this effect. This inhibitory effect was not overcome with the phosphatase inhibitors sodium orthovanadate or okadaic acid. Addition of receptor agonists SS or octreotide resulted in a dose dependent 2-3 fold stimulation of HDC-Iuc activity. SS mediated stimulation in stably transfected cells was not altered by overexpression of GiQtl and Gia 3, suggesting that this paradoxical effect was not due to a lack of these subunits in AGS-B cells. Conclusions: SSTR2 has an inhibitory effect on HDC transcription in basal and stimulated AGS-B cells. This inhibition by the receptor is not mediated through a phosphatase pathway. Addition of agonists SS and octreotide produces a dose dependent stimulation in transcription of HDC. This is not due to a lack of the appropiate G i subunits in AGS-B cells. SS stimulates HDC transcription independently of G i pathway in AGS-B cells.

CAMP-dependent signaling pathways regulate the human histidine decarboxylase promoter through activation of MAPK/ERK-cascades in gastric cancer cells

cAMP-dependent signaling pathways regulate the human histidine decarboxylase promoter through activation of MAPK/ERK-cascades in gastric cancer cells

Gastrin and Phorbol 12-Myristate 13-Acetate Regulate the Human Histidine Decarboxylase Promoter through Raf-dependent Activation of Extracellular Signal-regulated Kinase-related Signaling Pathways in Gastric Cancer Cells

Gastrin stimulates transcription of the human histidine decarboxylase (HDC) gene through binding to the G-protein-coupled cholecystokinin-B/gastrin receptor. We have explored the possibility that mitogen-activated protein kinase cascades play a role in mediating the effects of gastrin on transcription in a gastric cancer (AGS-B) cell line. Gastrin and phorbol 12-myristate 13-acetate (PMA) treatment of AGS-B cells was found to increase the phosphorylation of tyrosine residues of extracellular signal-regulated kinases (ERKs) 1 and 2 and increase ERK activity as determined by the in vitro phosphorylation of myelin basic protein. Reporter gene assays also demonstrated that gastrin and PMA stimulated Elk-1- and c-Myc-dependent transactivation, consistent with gastrin- and PMA-induced activation of ERKs. Overexpression of wild type ERK-1 and ERK-2 or activation of endogenous ERKs using activated MEK-1 (mitogen-activated protein kinase kinase or ERK kinase) overexpression stimulated HDC promoter activity in a dose-dependent fashion. Interruption of the ERK-related pathway using expression vectors for kinase-deficient ERKs or an ERK-specific phosphatase (PAC-1) blocked gastrin- and PMA-stimulated HDC promoter activity. In contrast, inhibition of the Jun kinase pathway using an interfering dominant negative SEK-1 (stress-activated protein kinase/ERK-1) mutant did not inhibit HDC promoter activity. Furthermore, whereas gastrin stimulated phosphorylation of Shc proteins and association with Grb2, activation of the HDC promoter was not influenced by expression of dominant negative Ras (N15 or N17) proteins. However, gastrin stimulated Raf-1 kinase activity, and activation of the HDC promoter was blocked by coexpression of a dominant negative Raf-1 construct. Overall, these data demonstrate that gastrin regulates HDC transcription in a Rafdependent, Ras-independent fashion predominantly through activation of the ERK-related pathway.

Regulated expression of GATA-6 transcription factor in gastric endocrine cells

BACKGROUND & AIMS: GATA transcription factors may regulate gene expression in developing tissues, including gut epithelium. In the stomach, their expression has been linked to regulation of proton pump genes. However, GATA consensus sequences also occur in the promoter of the histidine decarboxylase gene, located in enterochrommafin-like cells. The aim of this study was to determine if GATA factors are located in gastric endocrine cells and to examine their expression during development and in response to changes in the gastric luminal environment. METHODS: Polymerase chain reaction cloning, Northern blot, and gel shift assays were used to examine GATA expression in gastric endocrine cells; changes in GATA messenger RNA during development and in response to fasting, feeding, and gastric achlorhydria were determined by Northern blot. RESULTS: GATA-6 was expressed strongly in rodent gastric endocrine cell fractions, in a human ECL cell tumor, and in an endocrine cell line (STC-1) derived from gut epithelium; proteins from STC-1 cells bound specifically to GATA consensus sequences in the human histidine decarboxylase promoter. GATA messenger RNA abundance was up-regulated during terminal differentiation of the rat stomach and on feeding after a fast. CONCLUSIONS: The GATA-6 transcription factor is expressed in gastric endocrine cells and is a potential regulator of gastric differentiation and of genes involved in the response to feeding. (Gastroenterology 1997 May;112(5):1559-67)

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.

The Human Histidine Decarboxylase Promoter Is Regulated by Gastrin and Phorbol 12-Myristate 13-Acetate through a Downstream cis-Acting Element

Transcriptional regulation of the human histidine decarboxylase (HDC) gene by gastrin and the phorbol ester phorbol 12-myristate 13-acetate (PMA) was studied using transient transfection of human HDC promoter-luciferase constructs in a human gastric carcinoma cell line (AGS-B) that expresses the human cholecystokinin-B/gastrin receptor. The transcriptional activity of the human HDC promoter was stimulated 3-4-fold by gastrin and 13-fold by PMA, effects that could be blocked by down-regulation or antagonism of protein kinase C. 5'- and 3'-deletion analysis demonstrated that the sequence responsible for gastrin- and PMA-stimulated transactivation (gastrin response element (GAS-RE)) was located in a region (+2 to +24) downstream of the transcriptional start site (+1) in the human HDC promoter and contained a palindrome (5'-CCCTTTAAATAAAGGG-3'). When ligated upstream of the herpes simplex virus 1 thymidine kinase promoter, a single copy of the GAS-RE was sufficient to confer responsiveness to gastrin and PMA. Electrophoretic mobility shift assays with specific competitors and factor-specific antibody supershifts showed that the labeled GAS-RE bound a novel nuclear factor(s). In addition, both gastrin and PMA increased binding of this factor to the GAS-RE. Hence, the palindromic GAS-RE site is sufficient to explain the gastrin/PMA responsiveness of the human HDC promoter and appears to bind a novel transcription factor.

Rat histidine decarboxylase promoter is regulated by gastrin through a protein kinase C pathway.

The enzyme L-histidine decarboxylase (HDC; 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 h 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. 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 stimulated the transcriptional activity of the rat HDC promoter three- to fourfold, 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 protein kinase C (PKC) with the phorbol ester phorbol 12-myristate 13-acetate (PMA) substantially elevated rat HDC promoter activity, whereas induction of Ca2+ -dependent signaling pathways with thapsigargin was without effect. Downregulation 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.

Gastrin regulates the histidine decarboxylase promoter through a PKC-dependent pathway

Gastrin regulates the histidine decarboxylase promoter through a PKC-dependent pathway