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Conservation of a Growth Hormone-Responsive Promoter Element in the Human and Mouse Acid-Labile Subunit Genes¹

Department of Pediatrics, Baylor College of Medicine (A.S., S.K.D., D.R.P.), Houston, Texas 77030; the Department of Animal Science, Cornell University (Y.R.B.), Ithaca, New York 14853; the Department of Pediatrics, The Nemours Children’s Clinic, Mayo Medical School (R.C.O.), Jacksonville, Florida 32207

Address all correspondence and requests for reprints to: Dr. David R. Powell, Texas Children’s Hospital, Feigin Center, MC# 3–2482, 6621 Fannin, Houston, Texas 77030. E-mail: dpowell{at}bcm.tmc.edu

	Abstract

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During extrauterine life, insulin-like growth factors (IGFs) circulate in a ternary serum complex with one IGF-binding protein-3 (IGFBP-3) or IGFBP-5 protein and with a single acid-labile subunit (ALS). GH increases levels of this ternary complex; in mice, this effect is achieved in part by the ability of GH to stimulate mouse ALS (mALS) transcription through an interferon--activated sequence-like element (GLE) in the mALS promoter. To begin studying how GH regulates human ALS (hALS) gene expression, we cloned the hALS gene and found that it spans approximately 3.3 kb of DNA at chromosomal region 16p13.3. The hALS gene has two exons separated by a 1235-bp intron, which is found at the identical site in rat and mouse ALS genes. Sequence analysis reveals that the hALS 5'-flanking sequence is homologous to the mALS promoter, and that the GH-responsive GLE in the mALS promoter is conserved in both sequence and location in the hALS gene. The region spanning from -755 to -4 bp 5' to the hALS ATG translation start codon directs expression of a luciferase reporter gene in primary rat hepatocytes, and GH increases reporter expression in the presence of the native, but not a mutant, GLE in the hALS promoter. These data suggest that GH stimulates hALS and mALS gene expression by a similar mechanism, which involves at least in part a conserved GLE in the ALS promoter.

	Introduction

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INSULIN-LIKE growth factor I (IGF-I) and IGF-II are approximately 7.5-kDa proteins that exhibit mitogenic, metabolic, differentiative, chemotactic, and antiapoptotic effects on many tissues and cell types (1, 2). IGFs often confer their effects in an autocrine/paracrine manner (1, 2). After birth, however, circulating IGFs also appear to be biologically important, as many effects of GH are mediated by IGF-I (1, 2, 3).

IGFs circulate in serum and other body fluids at higher molecular mass, tightly bound by a family of at least six IGF-binding proteins (IGFBPs) (4, 5, 6). During extrauterine life, most IGFs circulate at about 150 kDa in a ternary complex of one IGF peptide, one IGFBP-3 or IGFBP-5 protein, and an 86-kDa acid-labile subunit (ALS) (6, 7, 8, 9).

The human ALS (hALS) complementary DNA (cDNA) sequence predicts a protein with 18–20 leucine-rich repeats of 24 amino acids (10); also present are 7 asparagine-linked glycosylation sites, which are important for binding of ALS to IGFBP-3 (11). Binding of the IGFBP-3/IGF-I complex with ALS to form the serum ternary complex greatly prolongs the circulating half-life of IGF-I (12). This is in part due to the decreased ability of ternary complexes to cross the capillary endothelial barrier; also, binding of ALS to IGFBP-3 or -5 may prevent proteases from binding to and degrading these IGFBPs, with subsequent release of IGFs to tissues (1, 2, 13, 14, 15). In either case, IGFs in ternary complexes are not readily bioavailable; whether these complexes serve primarily as an IGF reservoir or as a way to prevent unwanted insulin-like metabolic effects of IGF peptides (1, 2) is unclear.

ALS is expressed in a tissue-specific pattern, with synthesis confined almost exclusively to parenchymal cells of the postnatal liver (16, 17). GH treatment increases ALS protein levels in serum and in medium conditioned by primary rat hepatocytes in vitro; these increases result from the ability of GH to induce ALS messenger RNA (mRNA) levels in rat hepatocytes in vitro and in vivo (18, 19, 20, 21, 22, 23). GH stimulation of ALS mRNA levels in liver of hypophysectomized rats is mediated at the level of ALS gene transcription (21).

The chromosomal genes for mouse ALS (mALS) and rat ALS (rALS) have been cloned (24, 25). They share a simple organization with the protein-coding and 3'-untranslated regions contained in two exons separated by a single intron, which is identically positioned in the ALS genes from these two species. The 5'-flanking sequences in these two ALS genes are also quite similar. In the mALS gene, approximately 2 kb of the 5'-flanking region demonstrated promoter activity when transfected into rat H4-II-E hepatoma cells or primary hepatocytes, and GH significantly increased promoter activity (21, 24, 26). GH responsiveness of the mALS promoter has been mapped to a single DNA motif resembling an interferon--activated sequence-like element (GLE) (26). The present studies characterize the location and organization of the hALS chromosomal gene and show that the hALS and mALS promoter regions are homologous. These studies also demonstrate that the GH-responsive GLE is 100% conserved in and is able to confer GH stimulation to the hALS promoter.

	Materials and Methods

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General methods
Oligonucleotides used for sequencing, site-directed mutagenesis, and PCR amplifications were synthesized by either Ana-Gen Technologies (Palo Alto, CA) or the Child Health Research Center Core Facility at Baylor College of Medicine (Houston, TX). All native and mutant sequences and construct orientations were determined by DNA sequencing either using Sequenase (U.S. Biochemical Corp., Cleveland, OH) in the dideoxy chain termination method (27) or by dye terminator automated sequencing performed by the Child Health Research Center Core Facility using an ABI/Perkin-Elmer Corp. automated sequencer (Palo Alto, CA).

Isolation of hALS cDNA
One microgram of human liver total RNA (CLONTECH Laboratories, Inc., Palo Alto, CA) was reverse transcribed using random hexamer priming and SuperScript II (Life Technologies, Inc./BRL, Rockville, MD). This material served as template for oligonucleotides primers 5'-CTTCCTCAAGGACAACGG-3' and 5'-TTCCTGAGGCTGAGGTAGC-3' in a PCR amplification using Taq polymerase (Life Technologies, Inc./BRL), resulting in a 300-bp hALS DNA fragment spanning from 1245–1544 bp of the published hALS cDNA sequence (10). This amplicon was visualized by 8% PAGE, cut from the gel, eluted, ethanol precipitated, and then amplified in a second round of PCR. The purified DNA product served as template for ³²P labeling of this 300-bp fragment using the same oligonucleotide primers and PCR conditions; labeled DNA was then used to screen a Unizap human liver cDNA library (Stratagene, La Jolla, CA) as described previously (28). As no full-length hALS cDNA was isolated, a SmaI/Bsu36I fragment (1578–1898 bp of the published sequence) from a partial hALS cDNA was ³²P labeled and used to screen a human liver 5'-STRETCH PLUS cDNA library (CLONTECH Laboratories, Inc.). A 2-kb hALS cDNA was isolated and subcloned into pSP73 using EcoRI. This cDNA, spanning from 30–2039 bp of the hALS sequence, was subcloned into M13mp19 at the EcoRI site. Oligonucleotide 5'-TACCGAGCTCGAATTCCATGGCCCTGAGGAAAGGAGGCCTGGCCCTG GCGCTGCTGCTGCTGT-3' was used to introduce the missing 29 bp of hALS coding sequence by site-directed mutagenesis using the Kunkel method, as described previously (29). The full-length hALS cDNA was subcloned into pBluescript II SK^- (Stratagene) at the EcoRI site, creating phALS.

Isolation of a human ALS genomic clone
A 1.5-kb SacII/EcoRI fragment spanning from 570-2039 bp of the hALS sequence was labeled with ³²P and used to screen a human placental genomic library constructed in phage EMBL 3 (CLONTECH Laboratories, Inc.) as described previously (30). A single hALS clone was plaque purified, cleaved with several restriction endonucleases, and transferred to filters. The filters were prehybridized, hybridized, and autoradiographed as described previously (30), using both the 1.5-kb SacII/EcoRI 3'-hALS cDNA fragment, and a 5'-EcoRI/SacII fragment spanning from 1–575 bp of the hALS cDNA sequence, as ³²P-labeled probes. A 4.8-kb KpnI/SacII fragment of the hALS clone, which hybridized with the 5'- but not the 3'-hALS cDNA probe, was then subcloned into pBluescript II SK^- at KpnI/SacII, creating pg5hALS. Partial DNA sequencing of this fragment revealed that the 3'-end was identical to a region of the hALS cDNA extending to the SacII site at bp 575 of the published hALS sequence (10). To further characterize the 3'-end of the hALS gene, the hALS DNA was used as template for oligonucleotide primers 5'-CTCAACCTCGGCTGGAATAG-3' and 5'-CGATTGCCTTTGCCTTTAATTG-3', which were used to PCR amplify the 3'-region of the hALS gene spanning from to 523-1998 bp of the published hALS cDNA sequence. This PCR product was subcloned into pCR2.1 (Invitrogen, San Diego, CA), creating pg3hALS.

Fluorescence in situ hybridization
The 4.8-kb KpnI/SacII fragment of the hALS clone was used to probe standard metaphase spreads obtained from the peripheral blood lymphocytes of a human male donor. Details of probe labeling, chromosome identification, fluorescence in situ hybridization procedures, and digital imaging and processing have been reported previously (31).

Plasmid construction
A 1.4-kb fragment containing the ALS promoter region was released from pg5hALS with SalI (5')/SphI (3'), subcloned into M13mp19 at these sites, and sequenced. A 0.8-kb fragment containing the proximal hALS promoter was released from m13mp19 with NcoI (5')/BamHI (3') and subcloned into the HindIII site 5' to the luciferase reporter gene in pGL3-Basic (Promega Corp., Madison, WI), creating p755hALS. A GLE spanning from 667–675 bp 5' to the hALS ATG translation start codon, which is 100% conserved in the mALS gene and confers GH stimulation to the mALS promoter (26), was mutated using oligonucleotide 5'-TGCAGCCCTGCCAG GCAACGTATCGTGAGGCTGGGGGCGGGGC-3'. The 0.8-kb hALS promoter fragment containing the mutated GLE was released from m13mp19 with NcoI (5')/BamHI (3') and subcloned into the HindIII site in pGL3-Basic, creating p755hALSmGLE. The construction of p703WT, which contains the proximal 703 bp of the mALS promoter 5' to the luciferase reporter gene in pGL3-Basic, has been described previously (26).

Cell culture and DNA transfection
Primary hepatocytes, isolated from male Sprague Dawley rats (250–300 g) by procedures approved by the Cornell University Institutional animal care and use committee, were plated in six-well plates at a density of 1 x 10⁶ cells/well and maintained as described previously (26). Hepatocytes were washed twice with serum-free modified William’s E medium (MWEM) and then transfected for 14 h with a 1-ml solution of serum-free MWEM containing 1.2 µg luciferase plasmid, 0.018 µg pCMV-SEAP, which controlled for transfection efficiency, and 15 µg lipofectin (Life Technologies, Inc./BRL). After transfection, cells were cultured for 48 h in MWEM in the presence or absence of 100 ng/ml bovine GH (bGH); for the first 24 h, MWEM was supplemented with Matrigel (Becton Dickinson and Co., Bedford, MA). At the end of this 48-h period, medium was assayed for luciferase activity as described previously (26) and for secreted alkaline phosphatase by chemiluminescence following the recommendations of the manufacturer (Tropix, Bedford, MA).

Expression of hALS
Plasmid pKG3226 contains the human ß-actin promoter, simian virus 40 polyadenylation signal, and neomycin phosphotransferase resistance gene (32). Full-length hALS cDNA was released from phALS and subcloned into pKG3226 with EcoRI; the resulting expression vector, pKG3226/hALS, was stably transfected into Chinese hamster ovary (CHO)-K1 cells as described previously (14). Cells were incubated in serum-free McCoy’s 5A medium, and the medium was then screened for hALS expression by immunoblot as described previously (14), using a 1:7500 dilution of goat antihuman ALS antibody (Diagnostics Systems Laboratories, Inc., Webster, TX). ALS partially purified from human serum on a hIGFBP-3 antibody column (14) was used as a positive control on the immunoblot.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Isolation of a hALS cDNA
A nearly full-length hALS cDNA was isolated from a human liver cDNA library as described in Materials and Methods. It spanned from 30–2039 bp of the published hALS cDNA and was identical to the published sequence (10). After the missing 29 bp of 5'-hALS coding sequence were added by site-directed mutagenesis, the full-length hALS cDNA was inserted into eukaryotic expression vector pKG3226 and transfected into CHO-K1 cells. Cells stably transfected with pKG3226/hALS expressed an approximately 85-kDa protein that comigrated with partially purified hALS and was recognized by hALS antiserum (Fig. 1); this protein was not expressed by cells transfected with pKG3226 alone (data not shown).

View larger version (44K): [in this window] [in a new window]   Figure 1. hALS expression. A full-length hALS cDNA was placed in the eukaryotic expression vector pKG3226. This construct was then stably transfected into CHO-K1 cells. Conditioned medium from three independent clones (lanes 1–3) was screened for hALS expression by immunoblot using a goat anti-hALS antibody. ALS partially purified from human serum (lane 4) served as a positive control. The estimated size of hALS, in kilodaltons, is shown on the left.

Partial sequencing of the 4.8-kb KpnI/SacII genomic fragment revealed a single 1235-bp intron beginning 17 bp 3' to the ATG translation start codon. To determine whether additional 3'-introns were present in the hALS gene, oligonucleotide primers were designed to PCR amplify the region of the hALS cDNA that spans from 532-1998 bp and contains the polyadenylation signal. These primers amplified an identical 1466-bp PCR product when either hALS or the hALS cDNA served as template, thus confirming the absence of additional introns in the hALS gene. The organization of the hALS gene is shown in Fig. 2.

View larger version (9K): [in this window] [in a new window]   Figure 2. hALS gene organization. This schematic diagram depicts the organization of the hALS chromosomal gene. The 5'-flanking region (5FR) is represented by the white rectangle to the left of the ATG translation start codon; the location of the GLE within this region is shown. Exons 1 and 2 (E1 and E2) are represented by gray rectangles to the left and right of the black rectangle that represents the single intron (I). Arrows indicate the locations of selected restriction sites. Nucleotide sequence of the chromosomal region depicted here has been submitted to GenBank/EMBL data bank with accession number AF192554.

View larger version (116K): [in this window] [in a new window]   Figure 3. Chromosomal localization of the hALS gene. Fluorescence hybridization of a 4.8-kb hALS genomic fragment to standard human metaphase chromosomes. Fluorescent signals can be seen on both chromatids of each chromosome 16.

View larger version (77K): [in this window] [in a new window]   Figure 4. Comparison of 5'-flanking regions among the human, rat, and mouse ALS genes. DNA sequence from the human ALS 5'-flanking region was aligned with homologous regions from rat (25 ) and mouse (24 ) ALS genes using the algorithm of Smith and Waterman (30 ). Gaps in any sequence are represented by a dot. Nucleotides conserved between the hALS sequence and either the rALS or mALS sequence are represented by a dash. Numbers on the left refer to the distance, in base pairs, 5' (negative) to the A of the ATG translation start codon; for each ALS gene, this ATG codon is shown as the last 3 bp of sequence. The GH-responsive GLE spanning -675 to -667 bp of the hALS sequence is underlined.

View larger version (22K): [in this window] [in a new window]   Figure 5. Effect of GH on hALS promoter activity. DNA fragments spanning from -755 to -4 bp 5' to the hALS ATG translation start codon and containing either the native or mutant GLE were placed 5' to the luciferase reporter gene to create either p755hALS or p755hALSmGLE, respectively. These constructs were transiently transfected into primary rat hepatocytes and then cultured in serum-free medium in the presence or absence of 100 ng/ml bGH, as described in Materials and Methods. After 48 h, medium from each plate was assayed for luciferase activity. Activity of plasmids incubated without bGH were arbitrarily set at 100%; all values are presented as the mean ± SD and represent the results of two independent experiments performed in triplicate.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

The hALS gene is located on chromosomal region 16p13.3 near the -globin gene complex. Deletions of the 16p13.3 region are described in eight individuals with -thalassemia and mild to moderate mental retardation (34). In these cases, -thalassemia results from failure of the individual to inherit a normal -globin allele from one parent. In addition to -thalassemia and mental retardation, a variety of dysmorphic features are also described in these individuals. In general, their clinical phenotype is nonspecific, and short stature was present in only two of the eight patients. In mice, growth failure occurs with targeted inactivation of both, but not one, of the ALS alleles (Boisclair, Y. R., unpublished results). Thus, growth failure is unlikely to be a part of the -thalassemia/mental retardation phenotype, as these individuals have at least one ALS allele.

Although the rALS and mALS 5'-flanking regions share 87% nucleotide identity over the first 1318 bp of the mouse sequence, they apparently differ in the locations of their transcription start sites (24, 25). In the rALS gene, the major transcription start sites were located 447, 472, and 505 bp 5' to the ATG translation start codon. In contrast, the transcription start sites in the mALS gene clustered between 10–161 bp 5' to the ATG translation start codon, a region that is entirely contained within a known rALS cDNA sequence. This variability may be due to the fact that consensus TATA sequences, initiator sequences, or GC boxes, which serve to target the site of transcription initiation in most genes, are not conserved in the 5'-flanking regions of the ALS genes (24, 25). Transcription start sites were not mapped in the hALS gene due to lack of sufficient intact human liver RNA and to lack of human cell lines expressing ALS. However, comparing the known size of hALS mRNA transcripts in liver with the hALS cDNA sequence (10) suggests that hALS transcription start sites more closely approximate those in the mALS than the rALS gene.

Although rALS and mALS 5'-flanking regions are highly similar, they share only 51% and 47% nucleotide identity, respectively, with the proximal 1398-bp region of the hALS gene. However, the sequence spanning from -688 to -625 bp of the hALS 5'-flanking region is 81% and 77% conserved in the rALS and mALS 5'-flanking regions, respectively. The GLE that confers GH stimulation to the mALS promoter is present in this region of the mALS gene and is 100% conserved in the rALS and hALS genes (24, 25, 26), suggesting that this GLE participates in GH stimulation of hALS and rALS transcription. This hypothesis is supported by studies presented here, which show that GH does indeed stimulate the activity of the hALS promoter construct containing the native, but not the mutant, GLE. The effect of GH on mALS promoter activity appears to be mediated by members of the signal transducers and activators of transcription (STAT) protein family, STAT5a and STAT5b, which bind directly to this GLE in a GH-dependent fashion (26, 35). Considering that the GLE is 100% conserved in the hALS gene, it seems likely that STAT5a and STAT5b also confer GH stimulation to the hALS promoter. Although this hypothesis has not been tested, the data presented here provide strong evidence that GH uses a common mechanism to stimulate transcription of human and mouse ALS genes.

The significance of GH’s ability to more potently stimulate the mALS than the hALS promoter is unclear. Certainly, the transcriptional activity of STAT5 isoforms can be affected by the nature of surrounding DNA sequence (36, 37, 38). This suggests that although the GLE is necessary for GH stimulation of hALS and mALS promoter activity, nearby DNA elements and the proteins that they bind modulate STAT5 transcriptional activation and account for the differences in GH-stimulated activity of the mALS and hALS promoters. Based on these considerations, future studies will focus on identifying the proteins that interact to confer GH stimulation of hALS transcription.

	Footnotes

 
¹ This work was supported by NIH Grants RO1-DK-38773 (to D.R.P.) and RO1-DK-51624 (to Y.R.B.), and by the ß Research Fund, Houston City Council (to D.R.P.).

Received August 2, 1999.

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