Complete Coding Sequence, Promoter Region, and Genomic Structure of the Human ABCA2 Gene and Evidence for Sterol-Dependent Regulation in Macrophages

doi:10.1006/bbrc.2001.4305

Biochemical and Biophysical Research Communications

Volume 281, Issue 1, 16 February 2001, Pages 249-258

https://doi.org/10.1006/bbrc.2001.4305 Get rights and content

Abstract

Members of the human ABC transporter A subfamily have gained considerable attention based on the recent findings that ABCA1 and ABCR (ABCA4) cause familial HDL-deficiency syndromes and distinct forms of hereditary retinopathies, respectively. Here we report the complete cDNA and the genomic organization of ABCA2, another member of the human ABC A transporter subfamily. The ABCA2 coding region is 7.3 kb in size and codes for a 2436 amino acid polypeptide that bears the typical features of a full-size ABC transporter. Among the known members of the ABC A subfamily ABCA2 shares highest homology with the cholesterol-responsive transporters ABCA1 (50%) and the recently cloned ABCA7 (44%). The ABCA2 gene comprises 48 exons which are localized within a genomic region of only 21 kb. Analysis of the putative ABCA2 promoter sequence revealed potential binding sites for transcription factors that are involved in the differentiation of myeloid and neural cells. Gene expression analysis in human macrophages showed that ABCA2 mRNA is induced during cholesterol import indicating that ABCA2 is a cholesterol-responsive gene. Our results suggest a potential role for ABCA2 in macrophage lipid metabolism and neural development.

References (40)

B.E. Bauer et al.
Inventory and function of yeast ABC proteins: About sex, stress, pleiotropic drug and heavy metal resistance
Biochim. Biophys. Acta
(1999)
I. Klein et al.
An inventory of the human ABC proteins
Biochim. Biophys. Acta
(1999)
A. van Helvoort et al.
MDR1 p-glycoprotein is a lipid translocase of broad specificity, while MDR3 p-glycoprotein specifically translocates phosphatidylcholine
Cell
(1996)
M.F. Luciani et al.
Cloning of two novel ABC transporters mapping on human chromosome 9
Genomics
(1994)
W.E. Kaminski et al.
Identification of a novel human sterol-sensitive ATP-binding cassette transporter (ABCA7)
Biochem. Biophys. Res. Commun.
(2000)
E. Jendraschak et al.
Isolation of human promoter regions by Alu repeat consensus-based polymerase chain reaction
Genomics
(1998)
W.E. Kaminski et al.
Genomic organization of the human cholesterol-responsive ABC transporter ABCA7: Tandem linkage with the minor histocompatibility antigen HA-1 gene
Biochem. Biophys. Res. Commun.
(2000)
T. Langmann et al.
Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): Evidence for sterol-dependent regulation in macrophages
Biochem. Biophys. Res. Commun.
(1999)
C.R. Lincke et al.
Structure of the human MDR3 gene and physical mapping of the human MDR locus
J. Biol. Chem.
(1991)
D.G. Tenen et al.
Transcription factors, normal myeloid development, and leukemia
Blood
(1997)

H. Baumeister et al.

Identification of NFI-binding sites and cloning of NFI-cDNAs suggest a regulatory role for NFI transcription factors in olfactory neuron gene expression

Mol. Brain Res.

(1999)

M. Yasunami et al.

Molecular characterization of cDNA encoding a novel protein related to transcriptional enhancer factor-1 from neural precursor cells

J. Biol. Chem.

(1995)

S. Schneider-Maunoury et al.

Disruption of Krox-20 results in alteration of rhombomeres 3 and 5 in the developing hindbrain

Cell

(1993)

C.F. Higgins

ABC transporters: From microorganisms to man

Annu. Rev. Cell Biol.

(1992)

J. Klucken et al.

ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

Proc. Natl. Acad. Sci. USA

(2000)

G. Schmitz et al.

ABC transporters in cellular lipid trafficking

Curr. Opin. Lipidol.

(2000)

M. Bodzioch et al.

The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease

Nat. Genet.

(1999)

A. Brooks-Wilson et al.

Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency

Nat. Genet.

(1999)

S. Rust et al.

Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1

Nat. Genet.

(1999)

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ABCA11 is a pseudogene, and no orthologous counterparts for ABCA14–ABCA17 have been documented in the human genome [8]. mRNA levels of ABCA2, ABCA3 and ABCA7 in the ABCA subfamily were reported to be upregulated after sustained cholesterol influx [9,10], suggesting that ABCA transporters are involved in the transmembrane transport of endogenous lipids [11]. Transporters in the ABCA subfamily are thought to be involved in the transmembrane transport of cholesterol [12–14].
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^☆: Sequence data from this article have been deposited with the NCBI-GenBank Data Library under Accession Nos. AF327657–AF327705, respectively.

¹: To whom correspondence should be addressed at Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauß-Allee 11, D-93042 Regensburg, Germany. Fax: (+49)-941-944-6202. E-mail: [email protected].

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Regular ArticleComplete Coding Sequence, Promoter Region, and Genomic Structure of the Human ABCA2 Gene and Evidence for Sterol-Dependent Regulation in Macrophages☆

Abstract

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Cell

Genomics

Biochem. Biophys. Res. Commun.

Genomics

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Blood

Mol. Brain Res.

J. Biol. Chem.

Cell

ABC transporters: From microorganisms to man

Annu. Rev. Cell Biol.

ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

Proc. Natl. Acad. Sci. USA

ABC transporters in cellular lipid trafficking

Curr. Opin. Lipidol.

The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease

Nat. Genet.

Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency

Nat. Genet.

Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1

Nat. Genet.

Regular Article
Complete Coding Sequence, Promoter Region, and Genomic Structure of the Human ABCA2 Gene and Evidence for Sterol-Dependent Regulation in Macrophages☆