Department of Internal Medicine and Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, and Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, Texas 77030
Submitted 5 February 2004 ; accepted in final form 21 May 2004
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ABSTRACT |
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transcription; promoter; cAMP; potassium
The HK2 gene contains 23 exons and spans 23.5 kb of genomic DNA on chromosome 14C3 (38). It shares an exon-intron organization comparable to that of human ATP1AL1. Our laboratory (38) previously demonstrated that the proximal 177 bp of the 5'-flanking region of this gene confer basal transcriptional activity in mIMCD-3 cells and appear to be essential for collecting duct-selective expression. This proximal promoter region contains several consensus sequences for transcription factors that we have been systematically characterizing. Our laboratory (37) also has shown that NF-
, binding to a
DNA-binding element at 104 to 94, recruits histone deacetylase (HDAC)-6 to the DNA protein complex to suppress HK
2 transcription. Analysis of putative binding elements for transcription factors within the proximal promoter also revealed potential binding sites for cAMP-responsive element (CRE) binding (CREB) protein.
In the kidney, three different K+-ATPase activities, distinguished by their kinetic and pharmacological properties and adaptation to chronic K+ depletion, have been described. One activity (type I) is K+ dependent but not Na+ dependent, ouabain resistant, Sch-28080 sensitive, and expressed in collecting ducts. A second activity (type II) is K+ dependent but not Na+ dependent, Sch-28080 and ouabain sensitive, and expressed basally in proximal tubules and the thick ascending limbs. This activity is virtually abolished during chronic K+ depletion. A third activity (type III) is activated by either Na+ or K+ and exhibits higher sensitivities than type II activity to ouabain and Sch-28080 and a lower sensitivity than type I activity to Sch-28080. This activity is not expressed basally but is specifically upregulated in cortical collecting ducts (CCD) and outer medullary collecting ducts (OMCD) with chronic hypokalemia (15) and thus may represent the functional correlate of HK2.
Hormone signaling through cAMP/protein kinase A has been shown to rapidly stimulate type III K+-ATPase in principal cells of both CCD and OMCD and in OMCD intercalated cells in K+-depleted rats (15). To date, chronic effects of cAMP/protein kinase A on K+-ATPase activity have not been demonstrated. In addition to such nongenomic effects, cAMP mediates the hormonal stimulation of a number of eukaryotic genes through the binding of the CREB/activating transcription factor (ATF) family of proteins, members of the larger basic leucine zipper (bZIP) family of transcription factors, to a conserved CRE to recruit RNA polymerase to a promoter (17). CRE have been identified in numerous gene promoters and generally consist of minor variations in the 8-bp palindrome 5'-TGANNTCA-3' (7, 19, 28). The minimum sequence required for a functional CRE is the downstream half-site, 5'-NGTCA-3', although binding to this site is generally weaker and sequence exceptions have occurred (9). The trans-activation of genes through a CRE is proposed to occur by binding of phosphorylated ATF/CREB transcription factors to the CRE with recruitment of CREB binding protein (CBP) (5). The CREB family includes CREB-1, cAMP-responsive element modulatory (CREM) protein, and ATF-1. Whereas CREB and ATF-1 are ubiquitously expressed, CREM is expressed most highly in neuroendocrine tissues. Of the members of the CREB/ATF family, both CREB-1 and ATF-1 have been shown to be responsive to both the cAMP/protein kinase A and Ca2+/calmodulin-dependent protein kinase pathways (17).
We report here the identification of a defined region of the HK2 promoter required for vasopressin- and forskolin-stimulated, CREB-1-mediated transcription of the HK
2 gene in mIMCD-3 renal medullary collecting duct cells. We demonstrate that CREB-1, acting through CRE-like elements in the HK
2 86/60 region and without participation of the neighboring
element, significantly activates transcriptional activity of the HK
2 gene.
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MATERIALS AND METHODS |
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Quantitative real-time RT-PCR analysis of HK2 mRNA expression.
The assays were performed using the MJ Research DNA Engine Opticon 2 System (South San Francisco, CA). mIMCD-3 cells were incubated with vehicle or 108 M vasopressin for various times as indicated or with 15 µM forskolin or vehicle for 8 h, and total RNA was then extracted using RNA-Bee (Tel-Test, Friendswood, TX). The RNA was reverse transcribed to cDNA using the Superscript first-strand synthesis system for RT-PCR (GIBCO-Invitrogen). The cDNA was then quantified using quantitative RT-PCR with the DyNAmo SYBR green qPCR kit (Finnzymes). The HK
2 primers to amplify nucleotides +28 to +476 were forward, 5'-GGTGCCTTGTCTCTGTAAC-3', and reverse, 5'-GACCCTGGATGATGTTTG-3'. Normalization was performed using
-actin mRNA level as a housekeeping control. The
-actin primers were forward, 5'-GTGGGCCGCTCTAGGCACCAA-3', and reverse, 5'-CTCTTTGATGTCACGCACGATTTC-3', amplifying nucleotides +25 to +564. The specificity of these primer sets for their targets was confirmed by agarose gel electrophoresis. Each quantitative PCR assay was repeated three times, and the results were averaged.
Plasmids and constructs.
A series of deletion constructs of the murine HK2 proximal promoter beginning at nucleotide +253, which is between the transcription start site and the translation initiation codon ATG, and various lengths of the contiguous proximal 177, 477, 1,329, 2,833, 4,306, and 5,667 bp of the 5'-flanking region of the murine HK
2 gene nucleotides were previously described (38) and named pGL3-0.1mHK
2, pGL3-0.18mHK
2, pGL3-0.48mHK
2, pGL3-1.3mHK
2, pGL3-2.8mHK
2, pGL3-4.3mHK
2, and pGL3-5.7mHK
2. A PCR fragment spanning nucleotides +253 to 109 of the murine HK
2 proximal promoter was cloned into pGL3-Basic at the MluI and BglII sites to generate the construct pGL3-0.1mHK
2. pGL3-0.1mHK
2
86/60, which harbors mutated mHK
2 CRE-like sites at 86TGAGCTGC79, 79CGTCG75, and 65CGTGG61 in the 86/60 region (wild type 5'-TGAGCTGCGTCGCCCCAGGTACGTGGG-3' converted to 5'-TGAGAAGCGTTTCCCCATATACATGGG-3' with mutated bases underlined; Fig. 1), was generated by PCR using pGL3-0.1mHK
2 as a template. Plasmids CMV500, CREB, the dominant negative CREB mutant A-CREB (1), the constitutively active CREB mutant CREB-VP16 (25, 36), and pCREBdLZ-VP16, which is identical to CREB-VP16 except that the DNA-binding and dimerization domains of CREB are deleted (25), were a gift from Dr. D. D. Ginty (Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD). Plasmid glutathione S-transferase (GST)-CREB-1 (10) was a gift from Dr. T. F. Osborne (Department of Biology and Biochemistry, University of California, Irvine, CA). pGL3-0.1mHK
2
, which harbors a mutated NF-
site at the 104 to 94 position (5'-GGGGCGTCCCC-3' converted to 5'-TAGCCGTCCCC-3', mutated bases underlined) that ablates NF-
DNA-binding activity and enhancer activity was described previously (27).
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EMSA and supershift assays.
Double-stranded oligonucleotides corresponding to the CREB consensus oligonucleotide (5'-AGAGATTGCCTGACGTCAGAGAGCTAG-3'; Santa Cruz Biotechnologies), 28/74 (designated 0.1mHK2), and the HK
2 putative CREB binding region 86/60, derived from footprinting analysis, as well as the mutated 86/60 region (5'-TGAGAAGCGTTTCCCCATATACATGGG-3') used in the design of pGL3-0.1mHK
2
86/60, were end labeled with [
-32P]ATP using T4 polynucleotide kinase. Nuclear extracts were prepared from mIMCD-3 cells as detailed in earlier work done at our laboratory (37). GST-CREB fusion protein was harvested from Escherichia coli strain DH5
F after transfection with GST-CREB plasmid, according to previous work done at our laboratory (37). In the EMSA, 1.5 µg of recombinant CREB-1 DNA-binding domain (amino acids 254327) or 12 µg of mIMCD-3 nuclear extract was used. For the experiment in which the effect of forskolin was examined, nuclear extracts were prepared from mIMCD-3 cells treated for 2 h with either vehicle or 15 µM forskolin. In the supershift assay, 3 µg of GST-CREB or GST were preincubated with or without 4 µg of anti-CREB-1 antibody or IgG. Binding reactions were performed in binding buffer [10 mM Tris, pH 7.5, 50 mM NaCl, 0.1 mM EDTA, 1 mM dithiothreitol, 4% glycerol, and 1 µg poly(dI-dC)] for 1 h on ice by adding 1.75 pmol of duplex DNA probe (
2 x 105 cpm) in 20 µl of reaction binding buffer (Promega). In competition experiments to determine specificity, binding reactions were conducted in the presence or absence of a 50-fold molar excess of nonradiolabeled competitor oligonucleotides or an unrelated oligonucleotide (Sp1). In all cases, aliquots of the reactions were resolved on 4% native polyacrylamide gels in 0.5 M Tris-borate-EDTA buffer. The gels were dried and exposed to X-ray film with an enhancing screen at 70°C to detect the DNA-protein and DNA-protein-antibody complexes. Each observation represents a binding reaction performed in a new nuclear extract preparation. Experiments were replicated a minimum of three times.
Transient transfection and reporter gene assays.
mIMCD-3 cells grown in 24-well plates were transiently transfected using Lipofectamine 2000 reagent (Life Technologies) as detailed in previously published work performed in our laboratory (37). For comparative purposes, the cells were cotransfected with the Renilla luciferase expression plasmid pRL-SV40 (20 ng/well) to control for transfection efficiency and other assay-to-assay variability. Trans-repression/trans-activation experiments used 0.8 µg of pGL3-0.1mHK2, pGL3-0.18mHK
2, pGL3-0.48mHK
2, pGL3-1.3mHK
2, pGL3-2.8mHK
2, pGL3-4.3mHK
2, and pGL3-5.9mHK
2, as well as 0.1 µg of plasmids for CREB, CREB-VP16, CREBdLZ-VP16, A-CREB (1), or insertless expression vector CMV500. The functionality of the putative CRE in the 86/60 mHK
2 region was tested by transient cotransfection of pGL3-0.1mHK
2
86/60 or pGL3-0.1mHK
2
86/60 together with CREB-VP16. The potential involvement of the 104/94 NF-
site in CREB-mediated trans-activation of the HK
2 promoter was examined by transient cotransfection of pGL3-0.1mHK
2
together with CREB-VP16. Forty-eight hours later, firefly and Renilla luciferase activities in 5- to 10-µl lysate samples were measured in a Turner Systems 20/20 luminometer using the Dual-Luciferase reporter assay system according to the manufacturer's protocol. Firefly luciferase activity was normalized for Renilla luciferase activity in the lysates. The data were then normalized to the data of the parent vector pGL3 alone and recorded as HK
2 promoter activity.
Data analysis.
Potential regulatory motifs in the HK2 gene were identified with TESS: Transcription Element Search System software (http://www.cbil.upenn.edu/tess/tess33; Computational Biology and Informatics Laboratory, School of Medicine, University of Pennsylvania) using the TRANSFAC version 4.0 database. Quantitative data are expressed as means ± SE and were analyzed for statistical significance using ANOVA. P < 0.05 was considered significant.
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RESULTS |
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DISCUSSION |
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The effect of CREB-1 on the promoter was direct and mediated principally by DNA-binding because the 86/60 region was specifically footprinted in vitro by GST-CREB-1 (Fig. 4), and mutation of this DNA sequence disrupted the CREB DNA-binding activity (Fig. 5D) as well as abrogated CREB-mediated trans-activation of the HK2 promoter (Fig. 3A). The binding of proteins to the 86/60 region was specific because the formation of the major complexes was inhibited by the addition of excess unlabeled sequence but not by an excess of unlabeled sequence in which the CRE-like elements were mutated (Fig. 5C). However, because anti-CREB-1 antibody did not completely disrupt the 86/60 DNA-protein complex in supershift assays (Fig. 5, A and C), other transcription factors or coregulatory proteins may contribute, quantitatively to a much lesser degree, to the complex. Further studies are needed to identify such proteins.
Promoter regions of eukaryotic genes are generally composed of multiple binding sites for transcriptional activators and repressors that act in combination to regulate the expression of a linked gene. Our analysis of the proximal promoter of the HK2 gene has thus far revealed two functional elements: a
element at 104/94 that binds NF-
, as well as the CRE-like elements at 86/60 that bind CREB-1 reported here. The 104/94
element does not appear to participate in the CREB-mediated trans-activation of the HK
2 promoter, because an HK
2 promoter harboring a mutated 104/94
element exhibited trans-activation by CREB-VP16 comparable to that of the wild-type HK
2 promoter. Activator protein AP-2, which has a consensus binding site in this general region, also is not involved, because our laboratory previously showed by in vitro DNase I footprinting that this transcription factor does not footprint this region (37). Whether other CREB/ATF family members participate in HK
2 gene regulation remains unknown. The transcriptional coactivator CBP and closely related p300 are known to function as bridging factors between sequence-specific transcriptional activators and basal transcriptional machinery and to assemble them into multiprotein complexes. CBP/p300 also possesses intrinsic histone acetyltransferase (HAT) activity, which increases the accessibility of the basal transcriptional machinery to the promoter and activates transcription (33). Interestingly, our laboratory has already established that histone acetylation is important for activation of HK
2 promoter activity because interaction and recruitment of HDAC-6 to NF-
bound to the HK
2 promoter inhibits HK
2 promoter activity (37). Thus it will be interesting to determine whether CBP couples with CREB-1 bound in the 86/60 region and, through HAT activity, contributes to the trans-activation potential of CREB-1 on the HK
2 gene.
In addition to inducible effects, CREB-1 also trans-activates, to a much lesser degree, basal transcription of the HK2 gene through the 86/60 region. Overexpression of the dominant negative mutant A-CREB inhibited basal promoter activity of pGL3-0.1mHK
2 (Fig. 3B), and low levels of CREB-1 DNA-binding activity were apparent under basal conditions (Fig. 5B). It is known that CREB stimulates basal transcription of many CRE-containing genes in addition to its induction of target gene transcription upon phosphorylation by protein kinases. The basal activity of CREB resides in the constitutive activation domain (CAD) at the COOH terminus, whereas phosphorylation and inducibility map to a centrally located kinase-inducible domain (KID). The CAD interacts with a specific TATA binding protein-associated factor, which recruits a polymerase complex and activates transcription (13). In addition, in some cell types, interaction of CREB via its bZIP DNA binding/dimerization domain with the TORC (transducers of regulated CREB activity) family of coactivators promotes CRE-dependent transcription in a phosphorylation-independent manner (8). TORC recruitment appears to enhance the interaction of CREB with the polymerase complex without significantly altering CREB DNA-binding activity. Further studies are needed to define the specific mechanisms that underlie basal CREB-mediated HK
2 transcriptional activation in mIMCD-3 cells.
CRE are typically located in the proximal 100 bp of the TATA box in most genes, and the CRE-like elements described here also share proximity to the transcriptional initiation region. About half of the known genes with a functional CRE contain a full palindrome, with the other half containing a single CGTCA motif. However, several variations have been noted. For example, the TAT promoter contains a CRE that differs from the consensus sequence at the first three nucleotides (CTGCGTCA), and the c-fos promoter contains a CRE that differs from the consensus CRE by nucleotides in the seventh and eighth positions (TGACGTAG) (22). Sequence comparisons revealed three near-matches to the consensus CRE full and half-sites: 86TGAGCTGC79 is a 6/8 nucleotide match of the full palindrome, and 79CGTCG75 and 65CGTGG61 are both 4/5 nucleotide matches of the consensus CRE half-site. Mutation of all three sites dramatically limited CREB-1 binding to the 86/60 oligomer in the EMSA and the activity of the pGL3-0.1mHK-luc promoter construct, indicating that they are indeed functional CRE.
The specific roles of HK2 in the collecting duct in vivo are unclear. Because HK
2-null mice exhibit profound fecal rather than urinary K+ losses during K+ restriction (18), a major role in K+ reabsorption has not been convincingly established. However, as Meneton et al. (18) pointed out, the data do not rule out the possibility that HK
2 is involved in renal K+ conservation by further limiting urinary K+ losses. In their report, the mean values for daily K+ excretion were consistently
20% greater in the HK
2-null than in the HK
2 wild-type mice during chronic K+ restriction, although this difference was not statistically significant. However, because plasma K+ levels were 25% lower in the knockout mice, one would expect greater K+ conservation, not a trend toward less K+ conservation. Similarly, the specific physiological and pathophysiological roles for vasopressin-stimulated and CREB-mediated trans-activation of the HK
2 promoter in IMCD cells remain to be defined. It is known that chronic K+ deprivation, a strong stimulus for renal medullary HK
2 expression, causes impairment of urine-concentrating ability (2). Chronic K+ depletion has been shown to result in impaired sensitivity of cAMP production to vasopressin in the renal medulla as well as polyuria (4). This decrease in cAMP would also limit the stimulus for HK
2 gene transcription, as shown here. Thus the blunting of responsiveness to vasopressin in the medullary collecting duct would cause renal water losses and potentially aggravate the K+ depletion by limiting HK
2-mediated renal K+ conservation. Further physiological studies are required. In terms of acid-base balance, metabolic acidosis has been shown to be associated with an increase in AVP synthesis and secretion, with a resultant increase in aquaporin-2 expression and water reabsorption in the collecting duct (3). Such an increase in vasopressin levels would be expected to enhance HK
2 expression and H+-K+-ATPase-mediated H+ secretion that would facilitate correction of the metabolic acidosis.
We would like to have tested whether enhanced expression of HK2 by vasopressin and cAMP is associated with increased H+/K+ exchange activity in mIMCD-3 cells. However, we previously showed that Sch-28080 depletes intracellular ATP levels in mIMCD-3 cells and thereby indirectly inhibits all K+-ATPases (Na+-K+- as well as H+-K+-ATPase) (6). Because the method of distinguishing H+-K+-ATPase
1- and
2-subunits is based primarily on the Sch-28080 sensitivity of the former and the Sch-28080 insensitivity of the latter, we cannot specifically distinguish the two and cannot reliably distinguish the effects of the H+-K+-ATPase from those of the Na+-K+-ATPases in the presence of Sch-28080 in intact mIMCD-3 cells.
The data reported here highlight the complex transcriptional and posttranslational control of HK2 by vasopressin and cAMP/protein kinase A. The combination of rapid nongenomic effects (15) and delayed and sustained genomic effects provides the HK
2 gene with substantial versatility in meeting challenges to K+ and acid-base homeostasis.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
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