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Am J Physiol Gastrointest Liver Physiol 290: G1096-G1104, 2006. First published December 15, 2005; doi:10.1152/ajpgi.00199.2005
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HORMONES AND SIGNALING

Yin yang 1 (YY1) represses histidine decarboxylase gene expression with SREBP-1a in part through an upstream Sp1 site

Wandong Ai, Ying Liu, and Timothy C. Wang

Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York

Submitted 2 May 2005 ; accepted in final form 10 December 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
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.

gastrin regulation; transcription factors; transient transfection; Kruppel-like factor 4

HISTAMINE IS A BIOAMINE that plays an important role in many physiological processes, including allergy, inflammation, neurotransmission, and gastric acid secretion (4, 13, 35). Histidine decarboxylase (HDC) is the only known enzyme that converts histidine to histamine (31). HDC is expressed in many different cell types, including mast cells, skin cells, platelets, and basophils. However, in adult mammals, HDC is highly expressed in enterochromaffin-like (ECL) cells of the stomach, where HDC activity is tightly regulated by a gut peptide hormone, gastrin (22). HDC regulation occurs at both transcriptional and posttranslational levels, with the latter by proteolytic processing through the ubiquitin-proteasome pathway (11, 12, 18).

HDC promoter activity is upregulated by several different stimuli, including gastrin (45), PMA (21, 22, 32, 45), oxidative stress (20), thrombopointin (34), Helicobacter pylori infection (43, 44), and by neural peptide pituitary adenylate cyclase-activating polypeptide (PACAP) in PC12 cells through a cis element located at the –177- to –170-bp (relative to the transcriptional start site) region of the HDC promoter (30). Recently, Kruppel-like factor 4 (KLF4), formerly known as gut-enriched Kruppel-like factor, was shown to inhibit HDC promoter activity through three elements: an upstream GC box and two downstream gastrin-responsive elements (1), both of which are GC-rich sequences. Gastrin, a stomach peptide hormone, has been shown to activate gene expression through GC-rich sequences in the promoter. For example, gastrin-mediated upregulation of the chromogranin A promoter required an intact Sp1/Egr1-binding site (19). In addition, gastrin has been shown to upregulate the vesicular monoamine transporter-2 promoter through an AP-2/Sp1-binding site (14). Furthermore, the three gastrin-responsive elements in the HDC promoter are also GC rich and bind nuclear factors that have not yet been fully characterized (1, 36, 37). However, these studies have confirmed that the Sp1-binding GC boxes play an important role in both basal and regulated gene expression.

Sp1 was the first mammalian transcriptional factor to be cloned (26) that binds to GC-rich sequences, which include classic GC boxes (15), CACCC boxes (16), and basic transcription elements (25). It belongs to the "zinc finger" family of transcriptional factors containing at least 20 identified members in mammals, including Sp1 proteins, Sp1-Sp6, KLF1-KLF13, and kidney-enriched Kruppel-like factor. These transcriptional factors share high homology with each other at their COOH termini with three zinc fingers that are similar to those found in the Drosophila protein Kruppel (8). In general, Sp1 proteins bind with higher affinity to GC boxes than to CACCC boxes, whereas many of the KLFs bind preferentially to CACCC boxes over GC boxes. On the other hand, with a presence of a promiscuous sequence, the basic transcription element sequence binds many family members with more similar affinities. It is not surprising that all family members have the potential to affect "Sp1 site"-dependent transcription, given that all Sp/KLF factors bind with varying affinities to GC-rich sequences. For example, KLF4 competes with Sp1 in the regulation of HDC promoter activity, resulting in an Sp1-dependent inhibition of HDC expression (1). In addition, other zinc finger-containing transcriptional factors can also influence Sp1-mediated transcriptional activation by physical interactions. Yin Yang 1 (YY1) has been shown to interact with Sp1 through its first one and a half zinc fingers (27, 38) and to regulate gene expression through this interaction without direct binding of YY1 to its cognate DNA binding site in an artificial system (38).

YY1 is a pleiotropic transcriptional factor that can both upregulate and downregulate gene expression depending on the promoter context and the specific cellular environment (39, 42). It is a ubiquitously expressed 65-kDa protein that binds to a consensus 5'-CCATNTT-3' DNA sequence within viral and cellular promoters (2, 40). The mechanism of YY1 regulation of gene expression has been shown to be quite complex and most likely involves the coactivator and corepressor complexes containing histone acetyltranferases (HATs) and histone deacetylases (HDACs) through interactions with CBP/p300 and HDAC2, which possess chromatin-modification activities. In addition, although YY1 has been shown to bind DNA directly, it can regulate gene expression in a DNA binding- independent manner. For example, transiently expressed YY1 inhibits the sterol (SRE)-responsive element-binding protein (SREBP)-mediated activation of the LDL receptor in a sensitive and dose-dependent manner. This inhibition is independent of YY1 binding directly to the LDL receptor promoter (6). Interestingly, in this report, a competition was observed between YY1 and Sp1 with SREBP in the regulation of LDL receptor promoter activity, where Sp1 and SREBP appeared to synergistically activate the promoter as DNA binding proteins. Furthermore, other SREBP-regulated genes that are not coregulated by Sp1 are either not affected at all or are not as sensitive to the repression by overexpression of YY1 protein, suggesting a Sp1-dependent and YY1-induced transcriptional repression mechanism.

SREBPs are a family of transcriptional factors that regulate lipid homeostasis. They belong to the basic-helix-loop-helix-leucine zipper (bHLH-Zip) family. However, they differ from other bHLH-Zip proteins in that they are able to bind the typical E box-inverted DNA repeat (5'-CANNTG-3') as well as the direct DNA repeat of the SRE (for example, 5'-TCACNCCAC-3') (9). SREBPs have three isoforms designated SREBP-1a, SREBP-1c, and SREBP-2. SREBP-1a and -1c are derived from a single gene located on human chromosome 17p11.2 through the use of alternative transcriptional start sites that produce alternative forms of exon 1. SREBP-2 is derived from a different gene located on human chromosome 22q13 (9, 23). Functionally, it appears that SREBP-1 may be selectively involved in activation of genes involved in fatty acid metabolism and de novo lipogenesis, whereas SREBP-2 may be more selective for genes involved directly in cholesterol homeostasis (24, 33).

In this study, we used DNA affinity purification assays (DAPA) to show that YY1 binds the upstream Sp1-binding GC box in the HDC promoter and negatively regulates the promoter activity through this GC box. In addition, we demonstrated that a YY1 binder, SREBP-1a, represses HDC promoter activity in the same way as YY1 and the inhibition by YY1 and SREBP-1a requires both the upstream GC box and downstream gastrin-responsive elements. Furthermore, EMSAs showed that gastrin treatment reduces DNA binding activity of SREBP, suggesting that gastrin activation of HDC gene expression is partly mediated by downregulation of SREBP, a negative regulator of HDC gene expression.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Construction of plasmids. Cytomegalovirus (CMV) promoter-driven YY1 construct and the vector were kindly provided by Drs. A. Roman and K. Walsh (17). CMV promoter-driven SREBP-1a plasmid (designated as SREBP-1a), which encodes 1–490 amino acids of SREBP-1a, CMV promoter-driven SREBP-2 plasmid (designated as SREBP-2), which encodes 1–481 amino acids of SREBP-2, and vector (pCMV5) were kindly provided by Dr. T. Osborne (29). DNA sequences of these two truncation proteins from the constructs were subsequently cloned into pEP7 plasmid using HindIII and EcoRI sites (pEP-SREBP-1a and pEP-SREBP2, respectively). Construction of the minimal HDC promoter reporter constructs with and without mutations in the upstream GC box [107-bp HDC(Sp1M) and 107-bp HDC, respectively] was as described previously (1). Downstream gastrin-responsive elements truncated promoters with and without mutations in the upstream GC box [60-bp HDC(Sp1M) and 60-bp HDC, respectively] were constructed by direct cloning of the following two double-strand oligonucleotides with the KpnI and HindIII site at 5'- and 3'-ends into pGL2 firefly luciferase vector (pGL2-basic, Promega) predigested with the same enzymes (only the top strand was shown for each): 5'-GGAATTAATTAAACCTGGAGGAAGGGACTTTGAAGGGCGGAGCTAAGGTCAAAGAAAGAA-3', and 5'-GGAATTAATTAAACCTGGAGGAAGGGACTTTGAAGTTCGGAGCTAAGGTCAAAGAAAGAA-3'; upstream GC boxes in both oligonucleotides are underlined.

Cell culture and transient transfections. AGS-E cells were grown in complete medium (DMEM containing 10% FCS, 100 IU/ml penicillin, and 100 µg/ml streptomycin) in a humidified atmosphere (5% CO2). AGS-E cells were generated by stable transfection of AGS cells (ATCC CRL 1739) with the CCKB receptor. Transient transfections were performed using Superfect (Qiagen) according to the manufacturer's protocol. AGS-E cells were seeded to ~60% confluence in 12-well plates. Each well was transfected with 0.005 µg TK Renilla luciferase expression plasmid as an internal control, 0.5 µg different HDC reporter constructs, and 0.5 µg either different expression plasmids or empty vector. Three hours after transfection, medium was replaced with Ultraculture. Cells were stimulated the following day with gastrin (10–7 M) for the indicated times. If gastrin treatment was not needed, the cells were cultured in regular medium after transfection.

Luciferase assays of HDC reporter constructs. After incubation with or without gastrin, cells were washed with PBS and frozen at –80°C for at least 30 min to increase the efficiency of cell lysis. Cells were then transferred to room temperature and incubated with 250 µl of 1 x passive lysis buffer (Promega) for 20 min with constant shaking. Twenty microliters of the cell lysate were then assayed in a monolight luminometer, Monolight 3010 (Pharmingen). Light units of each reporter were divided by those of the internal control Renilla luciferase to represent the relative promoter activity.

Nuclear extract preparation and DAPA. Nuclear extract from AGS-E cells were prepared by the method of Dignam et al. (10), as modified by Lee et al. (28). The wild-type and GC box mutant 16-bp oligonucleotides biotinylated at the 5'-end (from Invitrogen) were annealed with the respective antisense oligonucleotides (see Fig. 2B). DAPA was performed as described previously (7, 41). Briefly, 50 µg nuclear extracts were mixed with 5 µg annealed biotinylated oligonucleotide in the binding buffer (20 mM HEPES, 10% glycerol, 50 mM KCl, 0.2 mM EDTA, 1.5 mM MgCl2, 10 µM ZnCl2, 1 mM DTT, and 0.25% Triton X-100; pH 7.9). The mixture was incubated on ice for 1 h and streptavidin agarose beads (preequilibrated with the binding buffer; Promega) were added, followed by an additional incubation at room temperature for 2 h with gentle agitation. The beads were washed four times with the binding buffer (15 min each), and the final pellet was resuspended with 1x SDS-PAGE-loading buffer and boiled for 5 min to elute the oligonucleotide-bound proteins. The bound proteins were loaded onto a SDS-PAGE gel, and Western blot analysis was then performed using anti-YY1 antibody (sc281; Santa Cruz Biotechnology).


Figure 2
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  		Fig. 2. YY1 inhibits the minimal HDC promoter activity through the upstream Sp1-binding GC box. A: cotransfection assays were similarly perform as described in Fig. 1 except for the usage of the wild-type minimal HDC promoter (designated as WT) and the mutant minimal promoter with mutations in the upstream GC box (designated as Sp1M). Statistical significance is shown similarly as in Fig. 1. B: wild-type and GC box mutant oligonucleotides and their relative position in the minimal HDC promoter are shown. The same GC box mutation was used through the whole study. C: DNA affinity precipitation assays (DAPA) on the GC box in the minimal HDC promoter. Nuclear extracts from AGS-E cells were incubated with the wild-type and mutant GC box oligonucleotides (biotinylated, designated as Sp1 and Sp1M) as shown in B. After incubation with streptavidin agarose beads, the bound proteins in the beads following wash were analyzed by Western blot analysis using anti-YY1 antibody. Total nuclear extract (5 µg) was used for Western blot analysis as the positive control (shown as total).

 
Total RNA preparation from AGS-E cells and quantitative real-time PCR. AGS-E cells were grown to 70% confluence in a 10-cm tissue culture dish. Cells were then starved with serum-free DMED overnight, followed by 10–7 M gastrin treatment at different time points. RNA was then isolated using TRIzol reagent (Invitrogen) in accordance with the manufacturer's protocol. After extraction, 5 µg of total RNA were then used as a template to synthesize the cDNA using the First Strand Synthesis Kit (Invitrogen). The cDNA from this synthesis was then used in quantitative real-time (RT) PCR analysis using the following primer pairs of human origin: SREBP-1aRT5 (5'-TGTGGCGGCTGCATTGAGAGT-3') and SREBP-1aRT3 (5'-ACCAGTCCCCATCCACGAAGAAAC-3') for the SREBP-1a gene;SREBP-2RT5 (5'-GCTGTGCGCTCTCATTTTACCAA-3') and SREBP-2RT3 (5'-GAAGGAACTCTGCTGCCCATCT-3') for the SREBP-2 gene; YY1RT5 (5'-CCCACGGTCCCAGAGTCCA-3') and YY1RT3 (5'-GTGTGCGCAAATTGAAGTCCAGT-3') for the YY1 gene; and GAPDH-5RT (5'-GACATCAAGAAGGTGGTGAAGC-3') and GAPDH-3RT (5'-GTCCACCACCCTGTTGCTGTAG-3') for the GAPDH gene.

EMSAs. Double-stranded oligonucleotides of consensus YY1 binding DNA sequences (sc-2533 for wild type and sc-2534 for mutant; Santa Cruz Biotechnology) and SREBP-binding sequences [5'-GCTGTCAGCCCATGTGGCGTGGCCGC-3' for wild type with the core binding sequences underlined (top strand), and 5'-GCTGTCAGCCAATCTGGCGTGGCCGC-3' for mutant (top strand)] (5) were first generated by annealing one full strand with another strand that has 5'-overhangs without dCTP and then radiolabeled using Klenow enzyme and [{alpha}-32P]dCTP. HDC GC box (HDC-Sp1) and Sp1 consensus oligonucleotides (Sp1) have been described previously (1). For EMSAs, 10 µg of nuclear extract from AGS-E cells were mixed with 1.0 µg poly(dA-dT) (Amersham) with and without unlabeled oligonucleotides in a 20-µl reaction volume containing (in mM) 20 HEPES (pH 7.9), 150 KCl, 1 EDTA, and 2 DTT and 5% glycerol (3). The reactions were incubated on ice for 15 min before the addition of 20,000–100,000 counts/min [{alpha}-32P]dCTP-labeled oligonucleohides. Mixtures were further incubated on ice for 10 min before being loaded onto a 0.5x Tris-boric acid-EDTA buffer-5% nondenatured polyacrylamide gel, and then electrophoresis was carried out at 250 V for 1.5 h at 4°C. The gel was then dried and exposed to a Fuji phosphoimaging screen overnight, and the screen was scanned using a phosphoimager (Fuji FLA-5000).

Coimmunoprecipitation assays. Total protein extracts from AGS cells were prepared using RIPA buffer [50 mM Tris·HCl (pH 7.4), 150 mM NaCl, 1% Nonidet P-40, 0.5% sodium deoxylcholate, 0.1% SDS, and 5 mM EDTA] plus protease inhibitors (Roche; catalog no. 11617900). Five micrograms of rabbit polyclonal Sp1 antibody (Upstate; catalog no. 07-124) and the same amount of control IgG were used to perform immunoprecipitation. Extensively washed immunoprecipitates were then separated on a SDS-PAGE gel and analyzed by Western blot analysis with mouse monoclonal YY1 antibody (Santa Cruz Biotechnology; catalog no. sc-7341).

In vitro transcription and translation of SREBPs and coimmunoprecipitation. TNT-coupled reticulocyte lysate system (Promega; catalog no. L4611) was used for one tube transcription/translation. Rabbit reticulocyte was mixed with 1 µg pEP, pEP-SREBP-1a, or pEP-SREBP-2 and T7 RNA polymerase, after which the amino acid mixture without methionine plus [35S]methionine was added. After 90 min, expression of proteins was characterized by SDS-PAGE and autoradiography. For the in vitro binding assay, 100 ng of purified YY1 proteins (from Austral Biologicals, catalog no. TA-150-1) were added to half of [35S]methionine-labeled proteins and the volume was brought to 500 µl with RIPA buffer. YY1 polyclonal antibody (Santa Cruz Biotechnology; catalog no. sc-281) was used for immunoprecipitation. Washed immunoprecipitates were then separated on a SDS-PAGE gel and characterized by autoradiography.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
YY1 inhibits HDC promoter activity. Previously, Sp1 was shown to activate the HDC promoter through an upstream GC box and KLF4 to inhibit the promoter mainly through the same GC box, suggesting an important role for the upstream Sp1-binding GC box in the regulation of the HDC promoter (1). Because YY1 could potentially regulate gene expression through interactions with Sp1, it was postulated that YY1 might also regulate the HDC promoter through the upstream Sp1-binding GC box. To test this hypothesis, the minimal 107-bp and the full-length 1.8-kb HDC promoter reporter constructs were cotransfected with either vector alone or with the YY1 overexpression construct. As shown in Fig. 1, overexpression of YY1 reduced the full-length HDC promoter activity to ~40% and reduced the minimal promoter activity to ~30% compared with vector overexpression, indicating that YY1 negatively regulates HDC promoter activity.


Figure 1
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  		Fig. 1. Yin yang 1 (YY1) inhibits histidine decarboxylase (HDC) promoter activity by cotransfection assays. HDC reporter constructs (0.5 µg; designated as 1.8-kb HDC and 107-bp HDC as described in MATERIALS AND METHODs) and internal control Renilla luciferase plasmid (0.005 µg) were cotransfected with 0.5 µg vector (pCMV; designated as CMV) or YY1 expression plasmid (pCMV-YY1; designated as YY1) into AGS-E cells. Forty-eight hours later, cells were harvested, and luciferase activities were assayed by a luminometer as described in MATERIALS AND METHODS. Means ± SD for 3 independent experiments are shown. Statistical difference of the relative promoter activities of the transfection experiments between cotransfected YY1 plasmids and the vector alone is significant (*P < 0.05).

 
The intact upstream GC box is required for YY1-dependent inhibition of the minimal HDC promoter Because no obvious YY1 consensus DNA binding sites were found in the minimal HDC promoter by sequence analysis, and because YY1 has been reported to inhibit transcription by competing with Sp1 (6), the requirement for an intact Sp1-binding GC box was tested for YY1-mediated HDC promoter inhibition. As shown in Fig. 2A, overexpression of YY1 inhibits the unaltered, minimal HDC promoter by more than threefold. Mutation of the upstream GC box significantly reduced the basal promoter activity as expected, because Sp1 is a very strong activator for basal transcription. It should be noted that the activity of the GC box mutant promoter is still much higher than that of the promoterless reporter gene (~5- to 10-fold higher, data not shown), indicating that it was active and should still be under proper regulation. Whereas YY1 inhibited the wild-type minimal HDC promoter, it did not inhibit the mutant promoter with mutations in the upstream GC box. In contrast, overexpression of YY1 upregulated the mutant promoter, suggesting that an intact upstream GC box is required for YY1 to inhibit HDC promoter. To further investigate the role of the upstream GC box in YY1-mediated inhibitory effect, the DNA binding activity of YY1 to this GC box was examined. DAPA showed that YY1 could be pulled down using a biotin-labeled wild-type GC-box oligonucleotide with little pulldown seen with the mutant GC box oligonucleotide (Fig. 2C). Taken together, these DNA binding data and cotransfection studies indicated that YY1 inhibits the minimal HDC promoter activity by binding to the upstream Sp1-binding GC box.

Sp1 competes with YY1 in the regulation of minimal HDC promoter. Because Sp1 was shown to activate the HDC promoter activity through the upstream GC box, the YY1-induced inhibition of the promoter through the same DNA element suggested a possible competition mechanism between Sp1 and YY1. To test this possibility, increasing amounts of an Sp1-expression construct were cotransfected with a fixed amount of the YY1 expression construct. As shown in Fig. 3, Sp1 dose dependently relieved the YY1-mediated HDC promoter inhibition. In a parallel cotransfection assay, YY1 dose dependently inhibited Sp1-mediated activation of a heterologous promoter construct (data not shown), supporting a model in which Sp1 competes, in an antagonistic way, with YY1 in the regulation of the minimal HDC promoter activity.


Figure 3
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  		Fig. 3. Sp1 competes with YY1 in the regulation of minimal HDC promoter activity. Cotransfection assays were performed with a fixed amount of CMV-YY1 construct (1.0 µg) and increasing amounts of CMV-Sp1 constructs, together with 0.25 µg of the minimal HDC promoter reporter construct. The total amount of plasmids in each transfection was filled with vector to 2.5 µg. The relative HDC promoter activity was calculated as described in Fig. 1. Statistical difference, *P < 0.05.

 
SREBP-1a and SREBP-2 inhibited the HDC promoter activity. Although our data suggest that Sp1 competes with YY1 in the regulation of the HDC promoter, the precise mechanism was not immediately clear. A competition mechanism between YY1 and Sp1 with SREBP was proposed in an earlier study of the regulation of LDL receptor promoter. To test the possible involvement of SREBP in regulating the HDC promoter, SREBP-1a and SREBP-2 were cotransfected with the minimal 107-bp HDC and the full-length 1.8-kb HDC promoter reporter constructs into AGS-E cells. As shown in Fig. 4A, overexpression of SREBP-1a reduced the full-length HDC promoter activity to ~10%, whereas overexpression of SRBBP-2 reduced promoter activity to ~3%. The same trend held true for inhibition of the minimal HDC promoter (~40% and ~10%, respectively). Additional cotransfection assays showed that YY1 further enhanced SREBP-1a- and SREBP-2-mediated HDC promoter inhibition (Fig. 4B).


Figure 4
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  		Fig. 4. SREBPs inhibit the HDC promoter activity by cotransfection assays. A: SREBP-1a, SREBP-2, and control vector were cotransfected with either 1.8-kb HDC or 107-bp HDC reporters into AGS-E cells. The relative HDC promoter activities were measured and calculated. Statistical difference, *P < 0.05, as described in Fig. 1. B: 0.05 µg of YY1 constructs (CMV, YY1) and 0.05 µg of SREBP constructs (pCMV5, SREBP-1a, SREBP-2) were cotransfected in combination with 0.25 µg of the minimal 107-bp HDC reporter into AGS-E cells. The relative HDC promoter activities were measured and calculated as described in Fig. 1. Statistical difference, *P < 0.05.

 
Inhibition of the minimal HDC promoter by overexpression of SREBP-1a and YY1 in an identical fashion. Unlike the LDL receptor promoter, which is also regulated by Sp1 and YY1, the minimal HDC promoter lacks a SREBP-binding site. Thus we next proceeded to identify the functional DNA elements in the minimal HDC promoter mediating the response to SREBP. On the basis of the primary structure of the wild-type HDC minimal promoter, several different HDC reporter constructs were made, with mutations in the upstream GC box [designated as 107 bp HDC (Sp1M)], truncation of the downstream gastrin-responsive elements (designated as 60-bp HDC), and a combination of both mutations [designated as 60-bp HDC (Sp1M); Fig. 5A]. SREBP-1a and SREBP-2 were cotransfected with these various HDC reporters. Interestingly, whereas overexpression of SREBP-1a and SREBP-2 inhibited the wild-type minimal HDC promoter, the degree of inhibition was greater for SREBP-2; in addition, the effects varied for the different HDC mutant reporters. SREBP-1a showed a statistically significant upregulation of the mutant HDC promoter with a mutated GC box, and this trend held true in cases where the downstream gastrin-responsive elements were truncated. Furthermore, when only the downstream gastrin-responsive elements were also truncated, SREBP-1a had no significant effect on HDC promoter activity. However, overexpression of SREBP-2 inhibited all of the various HDC promoter constructs (Fig. 5B). These results suggest that both the upstream GC box and the downstream gastrin-responsive elements are required for SREBP-1a-dependent inhibition of the HDC promoter activity and that SREBP-1a and SREBP-2 likely inhibit HDC promoter through somewhat different mechanism(s). Most strikingly, when the YY1 expression construct was similarly cotransfected with the various HDC reporter constructs, the effect of YY1 overexpression was the same as that of SREBP-1a (Fig. 5C). Given that a physical interaction between YY1 and SREBP-1a has previously been shown (6), these observations would strongly suggest that YY1 may interact with SREBP-1a to inhibit the HDC promoter.


Figure 5
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  		Fig. 5. SREBP-1a inhibits the minimal HDC promoter activity in the same way as YY1 by cotransfection assays. A: wild-type (107-bp HDC) and different mutant minimal HDC reporters are shown with mutations in the upstream GC box [107-bp HDC (Sp1M)], truncation of downstream gastrin-responsive elements (60-bp HDC), and combination of both [60-bp HDC (Sp1M)]. B: cotransfection assays were performed using 0.25-µg vector (pCMV5) or SREBP-1a or SREBP-2 with the different HDC reporter constructs as shown in A into AGS-E cells. The relative HDC promoter activities were measured and calculated as described in Fig. 1. Statistical difference, *P < 0.05. C: similar cotransfection assays were performed as described in B except that YY1 vector (CMV) and YY1 expression construct (CMV-YY1) were used.

 
Gastrin treatment decreased gene expression and DNA binding activity of SREBP. Gastrin was shown to activate HDC promoter activity through both the upstream GC box and the downstream gastrin-responsive elements (36, 37, 45). The requirement for these elements in the regulation of HDC promoter activity by YY1 and SREBP-1a raises the possibility that gastrin treatment might downregulate YY1/SREBP-1a activity. Expression of SREBP-1a, SREBP-2, and YY1 was first examined by quantitative RT-PCR using total RNA prepared from AGS-E cells after gastrin treatment for various times (30 min to 8 h). As shown in Fig. 6A, the mRNA levels of SREBP-1a and SREBP-2 were significantly reduced after gastrin treatment at all time points examined between 30 min and 8 h, whereas the expression of YY1 was essentially unchanged. These data suggest that gastrin downregulates the gene expression of SREBP-1a and SREBP-2 but not YY1. To test the significance of the downregulation of SREBP-1a and SREBP-2 by gastrin treatment, the DNA binding activities of SREBPs were tested by EMSAs using a specific SREBP-binding double-stranded oligonucleotide as the probe. As shown in Fig. 6B (lane 5), two specific DNA-protein complexes were observed (C1' and C2') that could be competed away by excess amounts of unlabeled wild-type but not by mutant SREBP-binding oligonucleotide (lanes 7 and 8). Interestingly, whereas the C1' complex did not change after gastrin treatment, the C2' complex was totally lost, suggesting that gastrin disrupts the formation of a subset of SREBP/DNA complexes. Consistent with the lack of gastrin effect on the YY1 mRNA level, the three specific DNA-protein complexes (C1, C2, and C3) in lane 1 (Fig. 6B), which bound to the YY1 consensus double-stranded probe, remained unchanged after gastrin treatment.


Figure 6
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  		Fig. 6. Gastrin treatment downregulated expression of SREBP-1a and SREBP-2 and the DNA binding activity of SREBPs. A: mRNA levels of SREBP-1a and SREBP-2, but not YY1, were downregulated by gastrin treatment. Total RNA from AGS-E cells was extracted at 30 min, 1 h, 2 h, and 8 h after treatment with 10–7 M gastrin. Reverse transcriptions were then performed followed by quantitative PCR using specific primers for SREBP-1a, SREBP-2, and YY1 as described in MATERIALS AND METHODS. The relative mRNA levels at each time point were normalized to the control nontreated samples at the 0 time point. One representative experiment from 3 independent experiments is shown here. B: DNA binding activities of SREBPs were disrupted by gastrin treatment. EMSAs were carried out by mixing nuclear extracts from AGS-E cells with radiolabeled consensus YY1 binding oligonucleotide (oligo) and SREBP-binding oligo. Lanes 1 and 5 show the results of the binding assay with nuclear extracts without gastrin treatment, and lanes 2 and 6 show the binding assay with nuclear extracts made from AGS-E cells after 24 h of 10–7 M gastrin treatment. Lanes 3, 4, 7, and 8 show competition assays in the presence of a 200-fold molar excess of unlabeled wild-type and mutant labeling oligos (lanes 3 and 4 for the wild-type and mutant consensus YY1 binding oligos, lanes 7 and 8 for the wild-type and mutant SREBP-binding oligos).

 
YY1 and SREBP-1a indirectly bind the GC box in the HDC promoter. The recruitment of YY1 to the GC box by DAPA assay (Fig. 2C) and the loss of inhibition of the HDC promoter activity by YY1 when the GC box is mutated suggest the importance of this DNA element in the regulation of the HDC promoter activity by YY1. To further study the identity of the association of YY1 with the GC box, EMSA was performed using a radiolabeled GC box oligonucleotide (HDC-Sp1 in Fig. 2B) and the nuclear extract from AGS cells. As shown in Fig. 7A, three major DNA-protein complexes were observed (C1–C3 in lane 2). Whereas they were efficiently competed away by unlabeled HDC-Sp1 (C1–C3 in lanes 3 and 4) and consensus Sp1-binding oligonucleotide (C1 and C2 in lanes 7 and 8), they remained intact by the competition with oligonuleotides that have the mutations in the core GC boxes (HDC-Sp1M and Sp1M, respectively), indicating the specific binding of Sp1 with this element. More importantly, the same amount of consensus YY1 and SREBP-binding oligonucleotides (Fig. 6B) did not show obvious competition in this assay, indicating that both YY1 and SREBP have much lower affinity with the GC box when compared with Sp1-binding oligonucleotide. Because YY1 was recruited to the GC box, we further tested the possibility that Sp1 recruits YY1 to the GC box by protein-protein interaction. Consistent with previous reports (27, 38), Fig. 7B showed that endogenous YY1 was pulled down by Sp1 antibody by immunoprecipitation. Similarly, in vitro transcribed and translated SREBP-1a was pulled down by YY1 (Fig. 7C, middle). Interestingly, SREBP-2 was pulled down by YY1 with a much lower efficiency in the same assay. Together, these data strongly suggest that YY1 and SREBP-1a were recruited to the GC box in the HDC promoter through protein-protein interactions.


Figure 7
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  		Fig. 7. YY1 and SREBP-1a bind the GC box of the HDC promoter by protein-protein interactions. A: YY1 and SREBPs have low affinity with the GC box of the HDC promoter. EMSAs were carried out by mixing nuclear extracts from AGS-E cells with a radiolabeled GC box in the HDC promoter (HDC-Sp1). Competition assays were performed using 50- and 200-fold molar excess of unlabeled oligos (lanes 3 and 4 for wild-type HDC-Sp1, lanes 5 and 6 for mutant HDC-Sp1M, lanes 7 and 8 for wild-type consensus Sp1 oligo, lanes 9 and 10 for mutant Sp1M oligo, lanes 11 and 12 for wild-type consensus YY1 oligo, and lanes 13 and 14 for SREBP-binding oligo). Specific C1, C2, and C3 DNA-protein complexes were observed (lane 2) without any competition. B: YY1 was pulled down by Sp1 antibody. Total protein extracts from AGS cells were immunoprecipitated by Sp1 antibody or control IgG, followed by Western blot analysis using YY1 antibody (A). Expression of endogenous YY1 and Sp1 in AGS cells were shown by Western blot analysis with YY1 and Sp1 antibodies (B). C: in vitro binding of SREBP-1a with YY1. pEP (Vector), pEP-SREBP-1a (SREBP-1a), and pEP-SREBP2 were produced by TNT system with [35S]methionine labeling as described in MATERIALS AND METHODS (top). Purified YY1 proteins were mixed with these in vitro proteins. Then, after YY1 antibody immunoprecipitation, the washed immunoprecipitates were separated by SDS-PAGE gel and characterized by autoradiography (middle). Bottom: equal amounts of YY1 protein were used in each immunoprecipitation using Western blot analysis.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In this study, we showed that the HDC promoter is downregulated by YY1 and SREBPs through the upstream GC box and the two downstream gastrin-responsive elements. Initial DAPA demonstrated that YY1, a multifunctional transcriptional factor, binds to the upstream GC box in the minimal HDC promoter. Further cotransfection assays showed that YY1 inhibits HDC promoter activity and that an intact upstream GC box is required for the inhibition of the minimal HDC promoter. As expected, YY1 competes in the regulation of the HDC promoter with Sp1, a known transcriptional activator with high affinity for GC boxes. In addition, cotransfection assays showed that both SREBP-1a and SREBP-2 [known as YY1 binders (6)] inhibit HDC promoter activity with an additive effect when YY1 was cotransfected. Mutation of the upstream GC box and truncation of the downstream gastrin-responsive elements showed that both elements are required for SREBP-1a to inhibit the HDC promoter. Interestingly, SREBP-1a and YY1 showed identical effects on various HDC promoter reporter constructs, strongly suggesting that they used the same mechanism to regulate HDC gene expression. Finally, gastrin, a stomach peptide shown to activate HDC promoter activity, downregulates gene expression and decreases the DNA binding activity of SREBPs, suggesting that gastrin activates HDC promoter activity at least in part through downregulation of SREBPs.

Our results demonstrated that there is a competitive antagonism between Sp1 and YY1 at the upstream GC box in the minimal HDC promoter, in which Sp1 activates and YY1 represses the promoter. Although Sp1 has been shown to bind directly to this DNA element, the direct binding of YY1 to this element is currently unknown, because DAPA only provides evidence of recruitment of YY1 to the element. Although the direct binding of YY1 with the element could not be ruled out because YY1 also has the zinc fingers at the COOH terminus that binds DNA, several lines of evidence support the indirect binding of YY1 with this GC box. First, there are no obvious consensus DNA binding sites for YY1 in the promoter by sequence analysis. Second, a physical interaction between YY1 and Sp1, and the recruitment of YY1 by Sp1 to a promoter GC box, has previously been reported (38) and confirmed in our system (Fig. 7B). Third, our DAPA studies indicated that YY1 was recruited the minimal HDC promoter specifically through the core Sp1 to binding GC box. Finally, our EMSA data suggest that YY1 has much lower affinity with the GC box compared with Sp1 (Fig. 7A). Thus our data would be consistent with the notion that YY1 inhibits the minimal HDC promoter by inhibiting Sp1-dependent activation of gene expression. The details of this functional antagonism between Sp1 and YY1 are not clear but most likely involve the displacement of Sp1 binding from the upstream GC box, because the YY1 interaction domain in Sp1 is located within the same COOH-terminal zinc finger region that is responsible for its DNA-binding activity (27).

Our studies also demonstrated that both SREBP-1a and SREBP-2 inhibit HDC promoter activity with somewhat different potency. In addition, SREBP-1a and YY1 (but not SREBP-2 and YY1) have the same effects on a variety of mutant HDC promoter reporters, supporting the notion that SREBP-1a and YY1 use a similar mechanism, possibly even as part of the same complex, to inhibit HDC promoter activity, because an interaction between SREBP-1a and YY1 has been demonstrated (6) and was also shown in our system (Fig. 7C). In these cotransfection assays, SREBP-1a and YY1 unexpectedly activated the mutant HDC minimal promoter with mutations in the core GC box (Fig. 5, B and C). At present, the mechanism for this upregulation of the mutational promoter is not entirely clear. Because there are no other obviously binding sites for either YY1 or SREBP-1a, one possibility is that SREBP-1a/YY1 are recruited to the minimal HDC promoter by another transcriptional factor resulting in the transcriptional activation when GC box is mutated. Alternatively, overexpression of SREBP-1a and YY1 may lead to the sequestration of other inhibitory proteins. It is not clear why the downstream gastrin-responsive elements are also required in the regulation of the HDC promoter by SREBP-1a/YY1, although these elements could conceivably provide a scaffold to stabilize the SREBP-1a/YY1 complex. In the absence of these downstream gastrin-responsive elements, the stable formation of SREBP-1a/YY1 inhibitory complex is disrupted, so that no obvious regulation is observed by SREBP-1a/YY1 (Fig. 5B). Unlike SREBP-1a, SREBP-2 inhibits the promoter activity of a variety of HDC promoter reporter constructs (Fig. 5B), suggesting that the SREBP family members modulate transcriptional activity through diverse mechanisms.

By quantitative RT-PCR analysis, gastrin treatment downregulates gene expression of the SREBPs. In addition, EMSAs showed that gastrin treatment disrupted the formation of a subset of SREBP/DNA complexes (Fig. 6B). Together with the interaction between YY1 and SREBP-1a, these observations might suggest that gastrin-induced HDC transcriptional activation is mediated in part through disruption of SREBP-1a/YY1 complex (see the proposed model in Fig. 8). The requirement of the downstream gastrin-responsive elements in SREBP-1a/YY1-mediated inhibition of HDC promoter provides a possible mechanism of how these downstream elements and the upstream GC box coordinately regulate HDC gene expression. Presumably, the SREBP-1a/YY1 inhibitory complex integrates both the upstream GC box and the downstream gastrin-responsive elements, as proposed in Fig. 8. Gastrin treatment disrupts the formation of this inhibitory complex by downregulation of SREBP, resulting in the upregulation of HDC promoter. Because SREBPs need to be proteolytically processed at the endoplasmic reticulum (ER) and then translocated to the nucleus to regulate gene transcription, gastrin can possibly regulate each of these steps as well. Therefore, gastrin could downregulate the DNA-binding activity of SERBPs by repressing their gene expression and/or inhibiting their proteolytic processing and/or their translocation from the ER to the nucleus. Nevertheless, to our knowledge, our current results provide the first clue of how gastrin regulates gene transcription in more detail through the GC box by downregulating gene expression of SREBP-1a.


Figure 8
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  		Fig. 8. Proposed model for the regulation of HDC promoter by YY1, SREBP-1a, and gastrin. YY1 forms a complex with SREBP-1a to inhibit the HDC promoter activity, most likely by competing and/or displacing Sp1 from the upstream GC box. Double line with arrowhead indicates that the downstream gastrin-responsive elements are required for the inhibition. Gastrin-induced HDC promoter activation is partly through the downregulation of SREBP-1a gene expression and DNA binding activity. See text for details.

 
In summary, we demonstrated that YY1 and SREBP-1a inhibit HDC promoter activity through both the upstream GC box and the downstream gastrin-responsive elements and gastrin activates HDC promoter at least in part by downregulation of gene expression of SREBPs. Additional studies will be needed to address the physiological significance of downregulation of the HDC promoter by SREBPs, because SREBPs are involved in lipid metabolism and cholesterol homeostasis. Finally, the interaction between SREBPs and YY1 and the precise mechanisms involved in gastrin downregulation of SREBPs are also worthy of further investigation.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
The work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1 DK-48077 (to T. C. Wang).


   ACKNOWLEDGMENTS
 
We thank Drs. A. Roman and T. Osborne for kindly providing CMV-YY1 plasmid and SREBP-1a and SREBP-2 plasmids.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. C. Wang, Division of Digestive and Liver Diseases, Columbia Univ. Medical Center, Irving Cancer Research Center, 1130 St. Nicholas Ave., Rm. 925, New York, NY 10032 (e-mail: tcw21{at}columbia.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Ai W, Liu Y, Langlois M, and Wang TC. Kruppel-like factor 4 (KLF4) represses histidine decarboxylase gene expression through an upstream Sp1 site and downstream gastrin responsive elements. J Biol Chem 279: 8684–8693, 2004.[Abstract/Free Full Text]
  2. Ai W, Narahari J, and Roman A. Yin yang 1 negatively regulates the differentiation-specific E1 promoter of human papillomavirus type 6. J Virol 74: 5198–5205, 2000.[Abstract/Free Full Text]
  3. Ai W, Toussaint E, and Roman A. CCAAT displacement protein binds to and negatively regulates human papillomavirus type 6 E6, E7, and E1 promoters. J Virol 73: 4220–4229, 1999.[Abstract/Free Full Text]
  4. Barocelli E and Ballabeni V. Histamine in the control of gastric acid secretion: a topic review. Pharmacol Res 47: 299–304, 2003.[CrossRef][ISI][Medline]
  5. Bennett MK, Lopez JM, Sanchez HB, and Osborne TF. Sterol regulation of fatty acid synthase promoter. Coordinate feedback regulation of two major lipid pathways. J Biol Chem 270: 25578–25583, 1995.[Abstract/Free Full Text]
  6. Bennett MK, Ngo TT, Athanikar JN, Rosenfeld JM, and Osborne TF. Co-stimulation of promoter for low density lipoprotein receptor gene by sterol regulatory element-binding protein and Sp1 is specifically disrupted by the yin yang 1 protein. J Biol Chem 274: 13025–13032, 1999.[Abstract/Free Full Text]
  7. Billon N, Carlisi D, Datto MB, van Grunsven LA, Watt A, Wang XF, and Rudkin BB. Cooperation of Sp1 and p300 in the induction of the CDK inhibitor p21WAF1/CIP1 during NGF-mediated neuronal differentiation. Oncogene 18: 2872–2882, 1999.[CrossRef][ISI][Medline]
  8. Black AR, Black JD, and Azizkhan-Clifford J. Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188: 143–160, 2001.[CrossRef][ISI][Medline]
  9. Brown MS and Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89: 331–340, 1997.[CrossRef][ISI][Medline]
  10. Dignam JD, Lebovitz RM, and Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11: 1475–1489, 1983.[Abstract/Free Full Text]
  11. Fleming JV, Fajardo I, Langlois MR, Sanchez-Jimenez F, and Wang TC. The carboxyl-terminus of rat L-histidine decarboxylase (HDC) specifically inhibits enzymatic activity and disrupts PLP-dependent interactions with L-histidine substrate analogues. Biochem J 381: 769–778, 2004.[CrossRef][ISI][Medline]
  12. Fleming JV and Wang TC. The production of 53- to 55-kDa isoforms is not required for rat L-histidine decarboxylase activity. J Biol Chem 278: 686–694, 2003.[Abstract/Free Full Text]
  13. Gelfand EW. Role of histamine in the pathophysiology of asthma: immunomodulatory and anti-inflammatory activities of H1-receptor antagonists. Am J Med 113, Suppl 9A: 2S–7S, 2002.[Medline]
  14. Gerhard M, Neumayer N, Presecan-Siedel E, Zanner R, Lengyel E, Cramer T, Hocker M, and Prinz C. Gastrin induces expression and promoter activity of the vesicular monoamine transporter subtype 2. Endocrinology 142: 3663–3672, 2001.[Abstract/Free Full Text]
  15. Gidoni D, Kadonaga JT, Barrera-Saldana H, Takahashi K, Chambon P, and Tjian R. Bidirectional SV40 transcription mediated by tandem Sp1 binding interactions. Science 230: 511–517, 1985.[Abstract/Free Full Text]
  16. Giglioni B, Comi P, Ronchi A, Mantovani R, and Ottolenghi S. The same nuclear proteins bind the proximal CACCC box of the human beta-globin promoter and a similar sequence in the enhancer. Biochem Biophys Res Commun 164: 149–155, 1989.[CrossRef][ISI][Medline]
  17. Gualberto A, LePage D, Pons G, Mader SL, Park K, Atchison ML, and Walsh K. Functional antagonism between YY1 and the serum response factor. Mol Cell Biol 12: 4209–4214, 1992.[Abstract/Free Full Text]
  18. Hirasawa N, Murakami A, and Ohuchi K. Expression of 74-kDa histidine decarboxylase protein in a macrophage-like cell line RAW 264.7 and inhibition by dexamethasone. Eur J Pharmacol 418: 23–28, 2001.[CrossRef][ISI][Medline]
  19. Hocker M, Raychowdhury R, Plath T, Wu H, O'Connor DT, Wiedenmann B, Rosewicz S, and Wang TC. Sp1 and CREB mediate gastrin-dependent regulation of chromogranin A promoter activity in gastric carcinoma cells. J Biol Chem 273: 34000–34007, 1998.[Abstract/Free Full Text]
  20. Hocker M, Rosenberg I, Xavier R, Henihan RJ, Wiedenmann B, Rosewicz S, Podolsky DK, and Wang TC. Oxidative stress activates the human histidine decarboxylase promoter in AGS gastric cancer cells. J Biol Chem 273: 23046–23054, 1998.[Abstract/Free Full Text]
  21. Hocker M, Zhang Z, Fenstermacher DA, Tagerud S, Chulak M, Joseph D, and Wang TC. Rat histidine decarboxylase promoter is regulated by gastrin through a protein kinase C pathway. Am J Physiol Gastrointest Liver Physiol 270: G619–G633, 1996.[Abstract/Free Full Text]
  22. Hocker M, Zhang Z, Koh TJ, and Wang TC. The regulation of histidine decarboxylase gene expression. Yale J Biol Med 69: 21–33, 1996.[ISI][Medline]
  23. Horton JD. Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem Soc Trans 30: 1091–1095, 2002.[CrossRef][ISI][Medline]
  24. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, and Goldstein JL. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 100: 12027–12032, 2003.[Abstract/Free Full Text]
  25. Imataka H, Sogawa K, Yasumoto K, Kikuchi Y, Sasano K, Kobayashi A, Hayami M, and Fujii-Kuriyama Y. Two regulatory proteins that bind to the basic transcription element (BTE), a GC box sequence in the promoter region of the rat P-4501A1 gene. EMBO J 11: 3663–3671, 1992.[ISI][Medline]
  26. Kadonaga JT, Carner KR, Masiarz FR, and Tjian R. Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell 51: 1079–1090, 1987.[CrossRef][ISI][Medline]
  27. Lee JS, Galvin KM, and Shi Y. Evidence for physical interaction between the zinc-finger transcription factors YY1 and Sp1. Proc Natl Acad Sci USA 90: 6145–6149, 1993.[Abstract/Free Full Text]
  28. Lee KA, Bindereif A, and Green MR. A small-scale procedure for preparation of nuclear extracts that support efficient transcription and pre-mRNA splicing. Genet Anal 5: 22–31, 1988.
  29. Magana MM and Osborne TF. Two tandem binding sites for sterol regulatory element binding proteins are required for sterol regulation of fatty-acid synthase promoter. J Biol Chem 271: 32689–32694, 1996.[Abstract/Free Full Text]
  30. McLaughlin JT, Ai W, Sinclair NF, Colucci R, Raychowdhury R, Koh TJ, and Wang TC. PACAP and gastrin regulate the histidine decarboxylase promoter via distinct mechanisms. Am J Physiol Gastrointest Liver Physiol 286: G51–G59, 2004.[Abstract/Free Full Text]
  31. Medina MA, Quesada AR, Nunez de Castro I, and Sanchez-Jimenez F. Histamine, polyamines, and cancer. Biochem Pharmacol 57: 1341–1344, 1999.[CrossRef][ISI][Medline]
  32. Ohgoh M, Yamamoto J, Kawata M, Yamamura I, Fukui T, and Ichikawa A. Enhanced expression of the mouse L-histidine decarboxylase gene with a combination of dexamethasone and 12-O-tetradecanoyl phorbol-13-acetate. Biochem Biophys Res Commun 196: 1113–1119, 1993.[CrossRef][ISI][Medline]
  33. Osborne TF. Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J Biol Chem 275: 32379–32382, 2000.[Free Full Text]
  34. Pacilio M, Debili N, Arnould A, Machavoine F, Rolli-Derkinderen M, Bodger M, Arock M, Dumenil D, Dy M, and Schneider E. Thrombopoietin induces histidine decarboxylase gene expression in c-mpl transfected UT7 cells. Biochem Biophys Res Commun 285: 1095–1101, 2001.[CrossRef][ISI][Medline]
  35. Rangachari PK, Prior T, Bell RA, and Huynh T. Histamine potentiation by hydroxylamines: structure-activity relations; inhibition of diamine oxidase. Am J Physiol Gastrointest Liver Physiol 263: G632–G641, 1992.[Abstract/Free Full Text]
  36. Raychowdhury R, Fleming JV, McLaughlin JT, Bulitta CJ, and Wang TC. Identification and characterization of a third gastrin response element (GAS-RE3) in the human histidine decarboxylase gene promoter. Biochem Biophys Res Commun 297: 1089–1095, 2002.[CrossRef][ISI][Medline]
  37. Raychowdhury R, Zhang Z, Hocker M, and Wang TC. Activation of human histidine decarboxylase gene promoter activity by gastrin is mediated by two distinct nuclear factors. J Biol Chem 274: 20961–20969, 1999.[Abstract/Free Full Text]
  38. Seto E, Lewis B, and Shenk T. Interaction between transcription factors Sp1 and YY1. Nature 365: 462–464, 1993.[CrossRef][Medline]
  39. Shi Y, Lee JS, and Galvin KM. Everything you have ever wanted to know about Yin Yang 1. Biochim Biophys Acta 1332: F49–F66, 1997.[Medline]
  40. Shrivastava A and Calame K. An analysis of genes regulated by the multi-functional transcriptional regulator Yin Yang-1. Nucleic Acids Res 22: 5151–5155, 1994.[Free Full Text]
  41. Singh J, Murata K, Itahana Y, and Desprez PY. Constitutive expression of the Id-1 promoter in human metastatic breast cancer cells is linked with the loss of NF-1/Rb/HDAC-1 transcription repressor complex. Oncogene 21: 1812–1822, 2002.[CrossRef][ISI][Medline]
  42. Thomas MJ and Seto E. Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key? Gene 236: 197–208, 1999.[CrossRef][ISI][Medline]
  43. Wessler S, Hocker M, Fischer W, Wang TC, Rosewicz S, Haas R, Wiedenmann B, Meyer TF, and Naumann M. Helicobacter pylori activates the histidine decarboxylase promoter through a mitogen-activated protein kinase pathway independent of pathogenicity island-encoded virulence factors. J Biol Chem 275: 3629–3636, 2000.[Abstract/Free Full Text]
  44. Wessler S, Rapp UR, Wiedenmann B, Meyer TF, Schoneberg T, Hocker M, and Naumann M. B-Raf/Rap1 signaling, but not c-Raf-1/Ras, induces the histidine decarboxylase promoter in Helicobacter pylori infection. FASEB J 16: 417–419, 2002.[Free Full Text]
  45. Zhang Z, Hocker M, Koh TJ, and Wang TC. The human histidine decarboxylase promoter is regulated by gastrin and phorbol 12-myristate 13-acetate through a downstream cis-acting element. J Biol Chem 271: 14188–14197, 1996.[Abstract/Free Full Text]



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