The ATP-binding cassette transporter ABCA2 as a mediator of intracellular trafficking

Abstract

ATP-binding cassette (ABC) transporters are a family of proteins that translocate molecules across cellular membranes. Substrates can include lipids, cholesterol and drugs. Mutations in ABC transporter genes can cause human pathologies and drug resistance phenotypes in cancer cells. ABCA2, the second member the A sub-family to be identified, was found at high levels in ovarian carcinoma cells resistant to the anti-cancer agent, estramustine (EM). In vitro models with elevated levels of ABCA2 are resistant to a variety of compounds, including estradiol, mitoxantrone and a free radical initiator, 2,2'-azobis-(2-amidinopropane) (AAPH). ABCA2 is most abundant in the central nervous system (CNS), ovary and macrophages. Enhanced expression of ABCA2 and related proteins, including ABCA1, ABCA4 and ABCA7, is found in human macrophages upon bolus cholesterol treatment. ABCA2 also plays a role in the trafficking of low-density lipoprotein (LDL)-derived free cholesterol and is coordinately expressed with genes involved in cholesterol homeostasis. Additionally, ABCA2 expression has been linked with gene cluster patterns consistent with pathologies including Alzheimer's disease (AD). A single-nucleotide polymorphism (SNP) in exon 14 of the ABCA2 gene was shown to be linked to early onset AD in humans, supporting the observation that ABCA2 expression influences levels of beta-amyloid peptide (Abeta), the primary component of senile plaques. ABCA2 may play a role in cholesterol transport and affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD, atherosclerosis and cancer.

Development of a Cell-Based, High-Throughput Screening Assay for Cholesterol Efflux Using a Fluorescent Mimic of Cholesterol

“…32,33 In the study presented herein, glyburide significantly reduced apoA-I-and HDL-induced cholesterol efflux, suggesting that the efflux of both F-Ch and 3 H-Ch is mediated by the same ABCA1 transporters. However, since other ABC family members, such as ABCA2, ABCA7, ABCG1, and ABCG4, also play roles in lipid trafficking [34][35][36][37][38] and glyburide's specificity is in doubt, a more specific method of inhibition, a neutralizing antibody to ABCA1, was also examined. These experiments clearly demonstrate that ABCA1 is the predominant transporter of F-Ch from MDFCs.…”

Direct and Coordinate Regulation of ATP-binding Cassette Transporter Genes by Myc Factors Generates Specific Transcription Signatures That Significantly Affect the Chemoresistance Phenotype of Cancer Cells

“…Moreover, ABCC4 is involved in human dendritic cell migration (38), and its expression is affected during hematopoietic stem cell differentiation (39). The ABCA2 transporter has been associated not only with drug resistance but also with disease severity at diagnosis in acute myeloid leukemia (40), and recent evidence suggests that it may be an important molecular marker of oligodendroglioma (41). Likewise, ABCF2, which has been reported to be a candidate marker for clear cell adenocarcinomas of the ovary, may also have a direct role in tumor development (42,43).…”

The biology of the ABCA3 lipid transporter in lung health and disease

“…Aside from the two nucleotide-binding domains (NBD1 and NBD2) found in every ABC transporter that serve as the functional unit for active substrate transport across membranes by utilizing the chemical energy of ATP hydrolysis (see (Linton, 2007) for review), two additional functional domains have been identified in the ABCA3 protein. First, the NH 2 terminal domain of all ABCA transporters, with the exception of one (ABCA10), harbor a signature targeting motif comprising five or six amino acids (xLxxKN or xLxKN) (Mack et al, 2006; Kaminski et al, 2006). This motif was found not to be a targeting determinant for the final deposition of ABCA transporters, but rather it functions to direct proteins to proximal post Golgi sorting vesicles (SVs) (Beers et al, 2011).…”