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Genomic Sequence and Structure of the Human ABCG1 (ABC8) Gene

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Abstract

The human ATP-binding cassette half transporter G1 (hABCG1) may play a role in cholesterol transport in macrophages. Using RACE assays we determined the structure of this gene. The hABCG1 gene spans more than 97 kb comprising 20 exons, 20 kb and 5 exons more than hitherto described. Four of the novel exons are upstream and one is downstream of previous exon 1, and they are predicted to encode at least five novel transcripts. We also detected two separate promoters, upstream of exons 1 and 5, respectively. The region 650 bp upstream of exon 1 was predicted to contain putative binding sites for SP1 and nuclear factor κB (NF-κB), but no sterol response elements (SREs) or retinoid X receptor (RXR) binding sites. The region 650 bp upstream of exon 5 contained 19 possible SP1 binding sites, one possible SRE, two possible NF-κB, and two putative RXR binding sites. Nevertheless, both promoters responded in macrophages to stimulation by hydroxycholesterol and retinoic acid.

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    Abbreviations used: 22(R)-HC, 22(R)-hydroxycholesterol; 9-cRA, 9-cis retinoic acid; aa, amino acid(s); ABC, ATP-binding cassette; ABCA1, ATP-binding cassette transporter A1; AP, activator protein; ATP, adenosinetriphosphate; bp, base pair(s); BRE, B recognition element; cAMP, cyclic-adenosinmonophosphate; C/EBP, CCAAT-enhancer-binding proteins; CREB, cAMP responsive element binding; CREBP, cAMP-responsive element binding protein; GCF, GC-binding factor; GM, granulocyte/macrophage; GR, glucocorticoid receptor; hABCG1, human ATP-binding cassette half transporter G1; HMG-CoA, hydroxymethylglutaryl coenzyme A; HNF, hepatic nuclear factor; IRF, interferon regulatory factor; ISGF, interferon-stimulated gene factor; ISRE, interferon-stimulated response element; LXR, liver-specific X receptor; mABCG1, murine ATP-binding cassette half transporter G1 (Mus musculus); MAZ, myc-associated zinc finger protein; NF-GMa, nuclear factor GMa; NF-κB, nuclear factor kappa B; NFY, nuclear factor Y (Y-box binding factor); N-Oct, nervous-system specific POU domain transcription factor binding to the octamer DNA motif; Oct, octamer transcription factor; RACE, rapid amplification of cDNA ends; RAR, retinoic acid receptor; RLM-RACE, RNA ligase-mediated rapid amplification of 5′ cDNA ends; ROR RAR-related orphan receptor; RXR retinoid X receptor; SP, stimulating protein; SRE, sterol response element; SREBP, sterol response element binding protein; T3R, thyroid hormone receptor; TCF, T-cell transcription factor; TFIID, transcription factor IID; TESS, Transcription Element Search Software; VDR, vitamin D receptor.

    1

    Stefan Lorkowski and Stephan Rust contributed equally to this paper.

    2

    To whom correspondence and reprint requests should be addressed at Ogham Diagnostics GmbH, Mendelstrasse 11, 48149 Münster, Germany. Fax: +49-251-9801389. E-mail: [email protected].

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