ATP-binding cassette (
ABC) transporters comprise a family of critical membrane bound
proteins functioning in the translocation of molecules across cellular membranes. Substrates for transport include
lipids,
cholesterol and pharmacological agents. Mutations in
ABC transporter genes cause a variety of human pathologies and elicit drug resistance phenotypes in
cancer cells. ABCA2, the second member the A subfamily to be identified, was highly expressed in ovarian
carcinoma cells resistant to the anti-
cancer agent,
estramustine, and more recently, in human
vestibular schwannomas. Cells expressing elevated levels of ABCA2 show resistance to variety of compounds, including
estradiol,
mitoxantrone and a
free radical initiator, 2,2'-azobis-(2-amidinopropane). ABCA2 is expressed in a variety of tissues, with greatest abundance in the central nervous system and macrophages. This transporter, along with other
proteins that have a high degree of homology to ABCA2, including ABCA1 and ABCA7, are up-regulated in human macrophages during
cholesterol import. Recent studies have shown ABCA2 also plays a role in the trafficking of
low-density lipoprotein (
LDL)-derived free
cholesterol and to be coordinately expressed with
sterol-responsive genes. A single nucleotide polymorphism in exon 14 of the ABCA2 gene was shown to be linked to
early onset Alzheimer disease (AD) in humans, supporting an earlier study showing ABCA2 expression influences levels of APP and
beta-amyloid peptide, the primary component of
senile plaques. Studies thus far implicate ABCA2 as a
sterol transporter, the deregulation of which may affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD,
atherosclerosis and
cancer.