The two isozymes of rat intestinal alkaline phosphatase are products of two distinct genes
Q. XIE and
D. H. ALPERS
Washington University School of Medicine, Division of Gastroenterology, St. Louis, Missouri 63110
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ABSTRACT
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Xie, Q., and D. H. Alpers. The two isozymes of rat intestinal alkaline phosphatase are products of two distinct genes. Physiol Genomics 3: 18, 2000.Rat intestinal alkaline phosphatases (IAP-I and -II) differ in primary structure, substrate specificity, tissue localization, and response to fat feeding. This study identifies two distinct genes (
56 kb) corresponding to each isozyme and containing 11 exons of nearly identical size. The exon-intron junctions are identical with those found in IAP genes from other species. The 1.7 and 1.2 bp of 5' flanking regions isolated from each gene, respectively, contain Sp1 and gut-enriched Kruppel-like factor (GKLF) binding sites, but otherwise show little identity. There is a potential CAAT-box 14 bp 5' to the transcriptional start site, 36 bp upstream from IAP-I, and a TATA-box 31 bp 5' to the transcriptional start site, 55 bp upstream from IAP-II. Transfection of these promoter regions (linked to luciferase as a reporter gene) into a kidney cell line, COS-7, produced the differential response to oleic acid expected from in vivo studies, i.e., threefold increase using the 5' flanking region of IAP-II, but not IAP-I. This response was not reproduced by 5,8,11,14-eicosatetraynoic acid (ETYA) or clofibrate, suggesting that peroxisome proliferator response elements are not involved. Isolation of the IAP-II gene will allow determination of the sequences responsible for dietary fat response in the enterocyte.
oleic acid response; promoter regions
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INTRODUCTION
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INTESTINAL ALKALINE PHOSPHATASE (IAP) is a late development in the alkaline phosphatase (AP) gene family, appearing first in mammals (16) and before placental AP appears in primates (10). All these IAPs are compact genes, contained within 56 kb. There are fetal and adult forms of human IAP (26), but only one gene for IAP has been found in human (12) and mouse (21). Evidence has been reported that human fetal and adult IAP are the same (1) and different (35) isozymes, but recent studies show that the two primary protein sequences are identical (8). A mouse embryonic AP has been cloned with a 75% identity to adult mouse IAP (21), but it is unlikely that this gene corresponds with the fetal IAP found in the human intestine. In the cow a single major gene was isolated (39), but at least three other unique IAP genes have been found (22). Thus, to date, multiple IAP genes have been reported only in the cow, but not in other species.
Most species express just a single IAP. The multiple forms of mRNAs encoding human IAP are due to differences in polyadenylation (12), and only one protein is produced. At least two protein isozymes have been reported in two species, the cow (3) and the rat (40). Polypeptide sequences predicted from cloned cDNAs encoding APs show that IAP and placental AP are 8790% identical (2, 12), whereas tissue nonspecific AP (TNAP) (i.e., liver/bone/kidney AP) shows 52% and 57% identity with placental AP and IAP, respectively (38). These findings are consistent with the hypothesis that a series of gene duplications is responsible for the development of the AP gene family. The first duplication from an ancestral gene may have produced the TNAP gene, and a subsequent duplication may have then caused further modifications to the placental AP, embryonic/placental-like AP, and IAP genes.
The rat intestine produces two isozymes of IAP, but unlike the near identity of isozymes in other species, these share only 79% identical amino acids (4, 31). Moreover, the differences are scattered equally throughout the mature proteins; thus gene splicing was not an adequate explanation. The isozymes appear at different times in postnatal development, have different substrate specificities, and respond differentially to cortisone or cortisone plus thyroxine (40). In addition, the larger mRNA transcript, IAP-II, is primarily duodenal in localization (40), and responds five times as much to triacylglycerol feeding as does IAP-I (6). Finally, the function of the two IAPs differs, as transfection of Caco-2 cells with rat IAP-II cDNA strongly stimulates secretion of a phospholipid-rich membrane from the enterocyte, whereas IAP-I is much less effective (33). These data suggested that two genes encoding rat IAP existed, and that they might be differentially regulated transcriptionally by fatty acids.
The present study reports the isolation in the rat of two genes encoding IAP with similar organization but different 5' flanking promoter regions. The promoter region of IAP-II, but not IAP-I, stimulated gene transcription in response to oleic acid, and this effect does not seem to be mediated by peroxisome proliferator-activated receptors (PPAR). The isolation of these genes provides the tools for further exploration of the physiological regulation of the more fatty acid-responsive IAP-II gene.
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MATERIALS AND METHODS
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Materials.
The GenomeWalker kits, rat genomic DNA, and SMART RACE cDNA Amplification kit were purchased from Clontech Laboratories (Palo Alto, CA). COS-7 cells (ATCC CRL 1650) were obtained from the ATCC (Rockville, MD). Oleic acid complexed with BSA, clofibrate, fetal calf serum, and fatty acid-free BSA were purchased from Sigma Chemical (St. Louis, MO), and 5,8,11,14-eicosatetraynoic acid (ETYA) was obtained from Biomol (Plymouth Meeting, PA). A construct containing three copies of the peroxisome proliferator response element from the acyl-CoA oxidase gene, placed upstream from a minimal TK promoter driving luciferase expression, was generously provided by Dr. Dan Kelly, Washington University School of Medicine, St. Louis, MO (35).
Isolation and characterization of genes.
Three separate genomic libraries were initially screened with DNA probes according to protocols supplied by the manufacturer (Stratagene, La Jolla, CA), using probes labeled with 32P by the random primer method. However, neither gene could be isolated with this technique. Therefore, a PCR-based method was selected. Using GenomeWalker kits (Clontech) with the proofreading polymerase, we isolated PCR-generated sequences, based on the cDNA sequences of the two rat IAP isozymes (4,19,31). Primers (Table 1) used to amplify sections of the clones were made in the Biotechnical Center, Washington University School of Medicine. For one section of the IAP-II gene that could not be isolated using GenomeWalker, the remaining gene portion was isolated using the Expand Long Template PCR (Boehringer Mannheim, Indianapolis, IN), which is composed of a unique enzyme mixture containing thermostable Taq and the proofreading Pwo DNA polymerases. PCR reactions were performed using a GeneAmp (model 2400; Perkin Elmer Applied Biosystems, Foster City, CA). PCR products were inserted into the pCR 2.1-TOPO vector (Invitrogen, Carlsbad, CA) prior to sequencing. All DNA segments were sequenced using the Applied Biosystems model 373A DNA sequencer. The potential transcription start sites of the two genes were identified by using the 5'-RACE PCR technique (Clontech). The IAP-I primer was -A129GTCTCCCTGCATGGTTGGGGCTATTGA-; for IAP-II the sequences were -C13TTGGCAACATTCAGGGCATCGGCT- and -CCTTTTGATTCCAGAAGACTGGGTTCTC-.
Construction of the reporter plasmids.
rIAP-II(-674).luc was constructed by PCR amplification of the rat IAP-II gene 5' flanking region from 11 to 674 bp upstream from the translation initiation codon and cloned into the promoter-less pGL3-basic plasmid (Promega, Madison, WI) between Sac I and Hind III. rIAP-I(-997).luc was created by PCR amplification of the rat IAP-I gene 5' flanking region from 4 to 997 bp upstream from the translation initiation codon and cloned into the promoterless pGL3-basic plasmid (Promega) between Sac I and Xho I. The PCR products were sequenced to confirm that the products were 100% identical to the template sequence.
Cell culture and transient transfection studies.
COS-7 cells were cultured in DMEM supplemented with 10% fetal calf serum in an atmosphere containing 5% CO2. The cells were plated in six-well tissue culture dishes at a density of 1.2 x 105 cells/well the day before transfection. For each transfection, the reporter plasmid and pHook-2lacZ (Invitrogen), a plasmid containing a ß-galactosidase gene downstream from the cytomegalovirus (CMV) promoter, were cotransfected into the COS-7 cells for monitoring the transfection efficiency. Transfection was performed using the FuGENE 6 transfection reagent (Boehringer Mannheim), with 1 µg of reporter plasmid DNA, 1 µg of ß-galactosidase plasmid DNA, and 6 µl of reagent added to cells grown to 4060% confluence in six-well Costar plates, in DMEM with 10% fetal calf serum added. Cells were harvested after 72 h (48 h after fat feeding), and the luciferase and ß-galactosidase assays were performed according to the manufacturers recommendations (Promega). Fluorescence was read in a Turner TD-700 fluorometer. Oleic acid was added already complexed with BSA at a molar ratio of 2:1, using serum-free DMEM with insulin-transferrin-selenium A supplement (GIBCO BRL; Life Technologies, Grand Island, NY). The expression response to various additions to the medium was normalized using BSA as a control.
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RESULTS
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Isolation and structure of the IAP-I and IAP-II genes.
Three separate genomic libraries were initially screened by rIAP-I and rIAP-II cDNA probes. Eight positive clones were identified in one of the libraries. However, all eight positive clones were an AP pseudogene, and neither rIAP gene could be isolated with this technique. Therefore, a PCR-based method with the proofreading polymerase was selected. The GenomeWalker technique produced the entire IAP-I gene in three fragments, but most of the exons of IAP-II were obtained from Expand Long Template PCR. Both genes are contained within 56 kb of sequence, comprising 11 exons (Fig. 1). Complete sequence can be access through GenBank (accession numbers: rIAP-I, AF227507; rIAP-II, AF227508). The intron/exon junctions were identical between the two isozymes, but there were small differences in the exon and intron lengths of the two genes (Table 2). These junctions are also the same as found in the human, bovine, and mouse IAP genes (14, 26, 47) (Fig. 2). The mouse and rat IAP-II sequence diverge from the others at residue 501, after the last exon/intron junction at residue 431 (Fig. 2). These two predicted protein structures contain uninterrupted runs of 15 and 17 threonine residues, respectively (except for isoleucine in position 3 in the mouse sequence), and these oligothreonine sequences occur at very similar locations in the carboxy terminus. The active sites of IAP appear to be well conserved among the various IAPs, although these are inferred for the mammalian enzymes from the only crystalline structure available, that of Escherichia coli (41). Nearly all of the residues that are considered important for metal binding in the bacterial enzyme are preserved in the rat IAPs, consistent with observation that both rat isoenzymes have good AP activity (40). These amino acid residues are also preserved in the bovine IAPs (22,39).

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Fig. 1. Cloning strategy, genomic organization, and restriction map of the IAP-I and IAP-II genes in the rat. The unilateral arrows show the fragments obtained by GenomeWalker. The bidirectional arrow shows the region obtained using Expand Long Template PCR. The open (white box) region of exon I represents the first 10 bp of the coding region and 65 bp (IAP-I) and 57 bp (IAP-II) into the 5' upstream region of each gene. The open (white box) region of exon XI represents that part of the 3'-untranslated region identified by comparing the cDNA sequences (19, 31). IAP, intestinal alkaline phosphatase.
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Fig. 2. Comparison of deduced amino acid sequences of human IAP (15), mouse IAP (26), bovine IAP (39), rat IAP-I, and rat IAP-II. Residues in common with human IAP are shown with black background. Intron/exon junctions are marked by asterisks. The residues involved in coordinating the metal ions Zn and Mg in E. coli AP are marked by arrow heads. The site for glycosylphosphatidylinositol linkage in human IAP may be D504 by analogy with D484 in human placental AP (25). For rat IAP-I the site is N511, and for IAP-II it is N533 (4). The right-angle arrow indicates the first amino acid of the mature protein.
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Comparison of the 5' flanking regions of the rat IAP-I and IAP-II genes.
Despite the similarity between the amino acid sequences (Fig. 2), and the genomic structure of the two IAPs (Fig. 1), the 5' flanking regions showed major differences (Figs. 3 and 4). Two likely transcription start sites were identified in IAP-I by the 5'-RACE PCR technique, beginning around bp -36 and -75. Just 5' to the most upstream site is a possible CAAT box starting at -86 or -90 (-ACAAAGTCCATCT-). One transcription start site was identified in IAP-I gene, beginning around bp -36. In the IAP-II gene a potential TATA box begins at bp -86 (-TATTTAA-). Both genes have a potential Sp1-related cis element (-GGGCGGG-), found in other IAP genes, starting at bp -660 in IAP-I and at bp -163 in IAP-II. The gut-enriched Kruppel-like factor (GKLF), capable of regulating expression of endogenous genes (39), interacts with a DNA sequence that is found in similar positions in the two genes, -182 in IAP-I and -214 in IAP-II. No full PPAR binding sites were found, but partial sites were present in many areas.

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Fig. 3. The 5'-flanking nucleotide sequence of the rat IAP-I gene. The transcription start sites identified by 5'-RACE procedure are marked with a right-angle arrow. The potential CAAT and TATA boxes are underlined and named, as are the CREB/ATF, AP1, GKLF, and Sp1 binding sites. Numbering starts in both directions from the first nucleotide of the translation start site (ATG). GKLF, gut-enriched Kruppel-like factor.
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Fig. 4. The 5'-flanking nucleotide sequence of the rat IAP-II gene. The transcription start site identified by 5'-RACE procedure is marked with a right-angle arrow. The potential TATA box is underlined and named, as are the GKLF and Sp1 binding sites. Numbering starts in both directions from the first nucleotide of the translation start site (ATG).
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Function of the 5' flanking regions in response to oleic acid feeding.
Previous study in our laboratory has demonstrated that fatty acids induce the expression of both rat IAPs, but especially rIAP-II (4). To determine whether this induction occurs at the transcriptional level, the plasmid containing the rIAP-I or rIAP-II gene promoter region fused to a luciferase reporter gene, rIAP-I(-997).luc and rIAP-II(-674).luc (see MATERIALS AND METHODS) was transiently transfected into COS-7 cells. The basal transcriptional activities of rIAP-I(-997).luc and rIAP-II(-674).luc in COS-7 cells were significantly higher than the promoterless vector backbone, but the IAP-II construct stimulated luciferase activity five times greater than that of the IAP-I chimer (data not shown). Figure 5 shows that oleic acid induced the transcriptional activity of rIAP-II(-674).luc, displaying a dose-dependent stimulation. However, luciferase activity was not stimulated by oleic acid added to rIAP-I(-997).luc transfectant. Increasing the 5' upstream region from IAP-I to 1672 bp from the translation start site did not produce a different result. To see whether the increased transcriptional activity of rIAP-II(-674).luc by oleic acid was mediated by PPARs, ETYA and clofibrate, both potent PPRE activators, were used to treat rIAP-II(-674).luc transfected COS-7 cells. Neither ETYA nor clofibrate increased the transcriptional activity of rIAP-II(-674). luc (Fig. 6). Cotransfection of COS-7 cells with rIAP-II(-674).luc and PPAR
and then treated with ETYA or clofibrate produced no effect. However, ETYA induced the transcriptional activity to 9.8-fold of that of a construct containing three copies of the peroxisome proliferator response element from the acyl-CoA oxidase gene (data not shown).

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Fig. 5. Rat IAP-II gene transcription is activated by oleic acid, but rat IAP-I gene transcription is not. Promoter-reporter constructs rIAP-I(-997).luc and rIAP-II(-674).luc were transiently transfected into COS-7 cells separately. The transfected cells were subsequently incubated for 48 h in serum-free medium containing oleic acid/albumin complex at the oleic acid (OA) concentrations of 50, 100, and 250 µM or BSA (vehicle) alone. The relative luciferase activity is expressed as the fold of the luciferase activity obtained from the OA treatment over BSA treatment. Data are means ± SD from at least 3 separate experiments performed.
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Fig. 6. 5,8,11,14-Eicosatetraynoic acid (ETYA) and clofibrate (Clof) treatment. Promoter-reporter construct rIAP-II(-674).luc was transiently transfected into COS-7 cells, which were subsequently incubated for 48 h in serum-free medium containing ETYA (10, 20, 50 µM) (A) or clofibrate (10, 50, 100 µM) (B). The bars represent relative luciferase activity (RLA) normalized (=1.0) to the luciferase activity in the presence of vehicle alone (DMSO for ETYA and EtOH for clofibrate). Data are means ± SD from at least 3 separate experiments performed.
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DISCUSSION
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The appearance of IAP occurs late in evolution (10,15), by gene duplication from a single ancestral gene (12, 21). The similarity of structure between the two rat IAP genes and IAP genes from other species is consistent with the analogy between the intron/exon positions of the tissue nonspecific, placental, and germ cell AP genes (15, 21, 38). Although the TNAP gene is much larger (
25 kb), the size difference is largely accounted for by repetitive intronic sequences. Thus gene duplication would seem to account for all the variants of AP genes to date. The human TNAP gene maps to chromosome 1 (29, 32), and the human placental, intestinal, and other related AP genes map to the distal long arm of chromosome 2, region 2q3437 (11, 23). The sheep and bovine IAP gene(s) is also located near the end of chromosome 2, as for the human chromosome 2 (18). In the mouse, however, two genes that hybridize with human IAP sequences are found on chromosome 1 (27). It is not clear whether these genes correspond with embryonic AP and IAP genes described in mouse (21).
Diversity in structure of the IAP proteins occurs in exon XI. Of special interest is the area in the rat IAP-II and the mouse IAP, where an oligothreonine sequence is inserted into the protein. This does not alter the membrane binding mechanism via the glycosylphosphatidylinositol linkage (5), although the site for linkage has been displaced toward the carboxy terminus (N533SA) compared with the site for human placental AP (D484; Ref. 25). The oligothreonine sequence may have an effect, however, on function or intracellular trafficking of the proteins.
The diversity in number, chromosomal location, and structure of AP genes in various species is intriguing for what it might mean functionally. The human TNAP contains more G and C residues (76%) (38) compared with IAP (60%) (12). These differences are partially due to the presence of an additional exon in the TNAP gene. Gene duplication along with alteration of their regulatory sequences would be a good mechanism for expressing different AP genes designed for different purposes. Knoll et al. (15) have proposed insertion and deletion events in the promoter regions of the three closely related human AP genes; intestinal, placental, and germ cell. However, the structure of the 5' flanking region of the two rat IAPs does not fit so neatly into this type of analysis. The three regions found in the human to be conserved by 67% or more, in clusters of 36, 74, and 126 bp, are not reproduced in the rat genes. Moreover, the two rat IAP genes do not show much identity with each other, except in one GC-rich area at about bp -120 to -160 in both genes. Thus it is reasonable that these promoter regions direct differential expression. These unique promoter sequences are reminiscent of the two totally different 5' flanking sequences found in the rat TNAP gene starting at bp -88 (34). It is possible that the mechanism for promoter "duplication" reflects the presence of two IAPs with different functions.
There are some interesting features of the two rat IAP isozymes that suggest functional differences, and these might be explained by differences in genomic as well as protein structure. IAP-II but not IAP-I is a potent stimulus to increasing IAP secretion attached to a phospholipid-rich membrane, surfactant-like particle (SLP) (23). This SLP plays a role in fat absorption (20, 41) and in binding of luminal bacteria (9). The membrane also is important in the interplay between luminal and tissue events, in that blocking SLP with antibody improves the outcome in experimental colitis in rats (7). The current studies confirm a difference in regulatory function of the 5' flanking region of the two rat IAP genes, one that mirrors the greater responsiveness of IAP-II to fat feeding in vivo. These results also suggest that IAP is regulated at the level of transcription.
IAP in HeLa cells is regulated at the level of transcription initiation (17). The Sp1 site found in all IAP genes is active in transcriptional regulation during in vitro differentiation in HT29 cells (14). At least three GC-rich regions in the first 136 bp of the 5' flanking region of the closely related germ cell AP are important for gene activation (37). Evidence exists from HeLa x fibroblast cell hybrids that a putative HeLa tumor suppressor gene may be a negative regulator of the IAP gene (24). The transcriptional activity of the promotor regions of rIAP-II induced by oleic acid, but not ETYA or clofibrate, suggest that fatty acid regulation of IAP gene transcription is not mediated by PPARs. Currently fatty acid regulation of gene expression in mammals has focussed on the response of somatic cells to dietary fat once it is enters the circulation from the gut (13). Isolation of the IAP-II gene that responds to fat feeding will allow determination of the 5' flanking sequences that are of greatest importance in the response to fatty acids in the intestine. The presence of a closely related gene, IAP-I, that does not respond to fat feeding may allow for easier recognition of key regulatory sequences.
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ACKNOWLEDGMENTS
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This work was supported by National Institutes of Health Grant DK-14038.
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FOOTNOTES
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Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).
Address for reprint requests and other correspondence: D. H. Alpers, Dept. of Medicine, Box 8124, Washington Univ. School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110 (E-mail: dalpers{at}im.wustl.edu).
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