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PubMed1998

Identification of three ABC transporter genes in Trypanosoma brucei spp.

ABC transporters are key players in the multidrug resistance of cancer cells and yeast, and they appear to be involved in the drug resistance of various pathogenic protozoa. No member of this ubiquitous protein family has yet been described in Trypanosoma brucei spp., the causative agents of African sleeping sickness and animal trypanosomiases. However, different cases of artificially induced drug resistance were shown to be linked to a reduction in net drug uptake. We used polymerase chain reaction with degenerate oligonucleotide primers corresponding to particularly conserved regions within the ATP-binding cassette to probe the genome of T. brucei spp. for the presence of ABC transporter genes. Three different sequence segments encoding ATP-binding cassettes were identified, which, upon Southern blotting, appeared to belong to distinct genes designated Tbabc1, Tbabc2, and Tbabc3. They appear to be single-copy genes in both drug-susceptible and drug-resistant stocks of T. brucei spp., expressed in bloodstream forms as well as in the procyclic life stage. Whereas Tbabc3 shows moderate homology to various known ABC transporters, Tbabc1 and Tbabc2 are highly homologous to P-glycoprotein A of Leishmania tarentolae and to the multidrug resistance protein 1 of L. donovani, respectively.

ATP-Binding Cassette Transporters↗

PubMed2004

Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) correspondence and conflicts with DSM-IV criteria in diagnosis of autism.

Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) are tests widely used for screening and diagnosis of autism. This study verified their correspondence and conflict with a diagnosis made with DSM-IV criteria. The sample consisted of 65 children, aged 18 months to 11 years. We found complete agreement between DSM-IV and CARS. We show that ABC does not distinguish individuals with autistic disorders from other cases of developmental disorders as well as CARS: the number of false negatives is high (46%) with ABC as opposed to 0% with CARS.

Autistic Disorder↗

PubMed2005

Rescue of folding defects in ABC transporters using pharmacological chaperones.

The ATP-binding cassette (ABC) family of membrane transport proteins is the largest class of transporters in humans (48 members). The majority of ABC transporters function at the cell surface. Therefore, defective folding and trafficking of the protein to the cell surface can lead to serious health problems. The classic example is cystic fibrosis (CF). In most CF patients, there is a deletion of Phe508 in the CFTR protein (DeltaF508 CFTR) that results in defective folding and intracellular retention of the protein (processing mutant). A potential treatment for most patients with CF would be to use a ligand(s) of CFTR that acts a pharmacological chaperone to correct the folding defect. The feasibility of such an approach was first demonstrated with the multidrug transporter P-glycoprotein (P-gp), an ABC transporter, and a sister protein of CFTR. It was found that P-gps with mutations at sites equivalent to those found in CFTR processing mutants were rescued when they were expressed in the presence of drug substrates or modulators of P-gp. These compounds acted as pharmacological chaperones and functioned by promoting interactions among the various domains in the protein during the folding process. Several groups have attempted to identify compounds that could rescue the folding defect in DeltaF508 CFTR. The best compound identified through high-throughout screening is a quinazoline derivative (CFcor-325). Expression of DeltaF508 CFTR as well as other CFTR processing mutants in the presence of 1 muM CFcor-325 promoted folding and trafficking of the mutant proteins to the cell surface in an active conformation. Therefore, CFcor-325 and other quinazoline derivates could be important therapeutic compounds for the treatment of CF.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Heterologous expression of a mammalian ABC transporter in plant and its application to phytoremediation.

Mammalian ATP-binding cassette (ABC) transporters involved in the multidrug-resistance of cancer cells can efflux cytotoxic compounds that show a wide variety of chemical structures and biological activities. Human multidrug resistance-associated protein (hMRP1) is one of the most intensively studied ABC transporters and many substrates have been identified, including both organic and inorganic compounds. In an attempt at novel 'transport engineering' using hMRP1 as a molecular pump, we established transgenic tobacco plants that showed clear resistance to cadmium and daunorubicin, although they were not resistant to etoposide, another known substrate of hMRP1. When expressed in tobacco cells, hMRP1 protein was localized at vacuolar membrane, while members of the MRP family are localized at plasma membrane in mammalian cells to reduce the cellular accumulation of various drugs. Thus, the hMRP1-expressing tobacco cells were able to take up these substrates across the tonoplast and sequestrate them in the vacuolar matrix. These results suggest that it may be possible to use the transgenic tobacco in phytoremediation, where a single transformation with an ABC transporter with broad substrate specificity should be effective for extracting various environmental pollutants including both organic and inorganic compounds, and accumulate them in the plant body. This should be advantageous for the remediation of a complex polluted environment, which is commonly found in the real world.

Antibiotics, Antineoplastic↗

PubMed1996

The ATP-binding cassette (ABC) gene family of Plasmodium falciparum.

Multidrug resistance (MDR) in mammalian tumour cells is mediated by P-glycoproteins. The apparent similarities between MDR and the chloroquine-resistance phenotype (CQR) in Plasmodium falciparum suggests that homologous proteins may be involved. In mammals, P-glycoproteins are encoded by mdr genes that are a subset of a super-family characterized by ATP-binding cassettes (ABC). Three genes, pfmdr1, pfmdr2 and pfef3-rl, have been identified in P. falciparum that have homology to the ABC transporter gene family. Each protein encoded by these genes has a distinct structure, suggesting functional differences between the three. Justin Rubio and Alan Cowman here discuss the structure and possible function of the ABC proteins from P. falciparum and evidence that the protein encoded by the pfmdr1 gene can influence quinoline-containing antimalarial drug-resistance phenotypes.

Journal Article↗

PubMed1983

Description of a mouse monoclonal anti-HLA-B27 antibody HLA-ABC-m3.

The production and characterization of a new anti-HLA-B27 monoclonal antibody HLA-ABC-m3 is described. This cytotoxic IgG2a antibody binds protein A and is able to precipitate cell surface molecules of 43,000 and 12,000 daltons corresponding to the HLA heavy chain and beta 2-microglobulin. Population testing revealed that the HLA-ABC-m3 antibody reacted with the peripheral blood lymphocytes of 47/47 individuals conventionally typed as HLA-B27+ and with 5/105 HLA-B27- individuals. These five extra reactions were with individuals expressing the cross-reactive HLA-B7 alloantigen, although the affinity of the monoclonal antibody for B27 heterozygous individuals (approx 10(9) M-1) was tenfold greater than with B7 individuals (approx 10(8) M-1). In addition, HLA-ABC-m3 reactivity segregated with HLA-B27 in two families. This monoclonal antibody should be of value in the investigation of the role of HLA-B27 in disease.

Animals↗

PubMed1987

Isolation and characterization of an induced chondroitinase ABC from Flavobacterium heparinum.

During the investigation of alternative methods for the large scale preparation of chondroitinases AC, B and C from Flavobacterium heparinum, a new chondroitinase activity was observed. This new enzyme, like the other chondroitinases, acts as an eliminase, forming unsaturated sulfated disaccharides from dermatan and chondroitin sulfates. In contrast to the chondroitinases previously described, which are endoglycosidases, this chondroitinase ABC cleaves the glycosidic linkages in an exolytic fashion, beginning at the reducing end of the substrate molecules. The oligosaccharides formed as transient products by the action of either chondroitinases or testicular hyaluronidase upon dermatan and chondroitin sulfates are also rapidly degraded by the chondroitinase ABC, regardless of their size or the presence of delta-4,5 unsaturation in the terminal uronic acid residue. The maximum activity of the chondroitinase ABC occurs at 30 degrees C and at pH 6.0-7.5. Only 15% of the activity was observed at 37 degrees C, indicating that the enzyme is very sensitive to thermal denaturation. It is strongly inhibited by phosphate ions and is also inhibited by the unsaturated disaccharides formed.

Chondroitin Lyases↗

PubMed2004

Molecular evolution of the ATPase subunit of three archaeal sugar ABC transporters.

The sequence of genes encoding extracellular amylopullulanase and putative maltodextrin ATP binding cassette (ABC) transporter of a hyperthermophilic archaeon, Thermococcus litoralis, was determined. The mdxK gene, which encodes an ATPase subunit of the putative maltodextrin ABC transporter, has extraordinarily high similarity with the malK gene, which encodes an ATPase subunit of trehalose/maltose ABC transporter of the same organism. DNA sequence comparison revealed that the malK gene was generated through the duplication of the mdxK gene before lateral gene transfer of the mal gene cluster from T. litoralis to Pyrococcus furiosus.

ATP-Binding Cassette Transporters↗

PubMed2004

Mining our ABCs: pharmacogenomic approach for evaluating transporter function in cancer drug resistance.

The association of transporter proteins and cancer drug resistance has been known for approximately 25 years, with recent discoveries pointing to an ever-increasing number of ATP binding cassette (ABC) transporter proteins involved with the response of cancer cells to pharmacotherapy. As reported in this issue of Cancer Cell, Szakács et al. couple quantitative, real-time PCR assays for all 48 human ABC transporters with chemosensitivity information mined from the NCI-60 cancer cell line database. Predictions of transporter involvement in drug effect were validated in selected cases, and furthermore produced novel leads relating ABC transporter expression and chemoresistance or chemosensitivity.

Antineoplastic Agents↗

PubMedDate not supplied

Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters.

Recent antitumor drug research has seen the development of a large variety of tyrosine kinase inhibitors (TKIs) with increasing specificity and selectivity. These are highly promising agents for specific inhibition of malignant cell growth and metastasis. However, their therapeutic potential also depends on access to their intracellular targets, which may be significantly affected by certain ABC membrane transporters. It has been recently shown that several human multidrug transporter ABC proteins interact with specific TKIs, and the ABCG2 transporter has an especially high affinity for some of these kinase inhibitors. These results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the treatment of cancer patients; moreover, the extrusion of TKIs by multidrug transporters may result in tumor cell TKI resistance. Interaction with multidrug resistance ABC transporters may also significantly modify the pharmacokinetics and toxicity of TKIs in patients.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

Possible involvement of plant ABC transporters in cadmium detoxification: a cDNA sub-microarray approach.

As a nontolerant plant to a large number of toxic compounds, Arabidopsis thaliana is a suitable model to study regulation of genes involved in response to heavy metals. Using a cDNA-microarray approach, we identified some ABC transporters that are differentially regulated after cadmium treatments, making them putative candidates for being involved in Cd sequestration and redistribution in plants. Regarding yeast and fission yeast, in which Cd is able to form complexes either with glutathione (GSH) or phytochelatins (PC) subsequently transported into vacuoles via ABC transporters, it is also very likely that some plant ABC transporters are able to transport GS(2)-Cd or PC-Cd complexes into subcellular compartments or outside of the cell. The characterization of such transporters is of great interest for developing molecular biology approaches in phytoremediation.

ATP-Binding Cassette Transporters↗

PubMed2005

ABC transporter architecture and regulatory roles of accessory domains.

We present an overview of the architecture of ATP-binding cassette (ABC) transporters and dissect the systems in core and accessory domains. The ABC transporter core is formed by the transmembrane domains (TMDs) and the nucleotide binding domains (NBDs) that constitute the actual translocator. The accessory domains include the substrate-binding proteins, that function as high affinity receptors in ABC type uptake systems, and regulatory or catalytic domains that can be fused to either the TMDs or NBDs. The regulatory domains add unique functions to the transporters allowing the systems to act as channel conductance regulators, osmosensors/regulators, and assemble into macromolecular complexes with specific properties.

ATP-Binding Cassette Transporters↗

PubMed2006

Peroxisomal ABC transporters.

Peroxisomes perform a range of different functions, dependent upon organism, tissue type, developmental stage or environmental conditions, many of which are connected with lipid metabolism. This review summarises recent research on ATP binding cassette (ABC) transporters of the peroxisomal membrane (ABC subfamily D) and their roles in plants, fungi and animals. Analysis of mutants has revealed that peroxisomal ABC transporters play key roles in specific metabolic and developmental functions in different organisms. A common function is import of substrates for beta-oxidation but much remains to be determined concerning transport substrates and mechanisms which appear to differ significantly between phyla.

ATP-Binding Cassette Transporters↗

PubMed2006

Genomics of plant ABC transporters: the alphabet of photosynthetic life forms or just holes in membranes?

The large number of ABC transporters in the Arabidopsis genome was made responsible for known as well as unexpected aspects in plant development. The combination of classical transport experiments with functional genomics approaches helped unravel some of these effects. Yet questions concerning the importance of this large number of ABC transporters in eukaryotic photosynthesizing organisms remain open. Phylogenomic analyses of whole genome sequence data reveal comparable sizes and composition between algae and higher plants within this protein family. Although this indicates the significance of ABC transporters in plants, several other questions remain to be answered.

ATP-Binding Cassette Transporters↗

PubMed2006

Lipidomic strategies to study structural and functional defects of ABC-transporters in cellular lipid trafficking.

The majority of the human ATP-binding cassette (ABC)-transporters function in cellular lipid trafficking and in the regulation of membrane lipid composition associating their dysfunction with human disease phenotypes related to sterol, phospholipid and fatty acid homeostasis. Based on findings from monogenetic disorders, animal models, and in vitro systems, major clues on the expression, function and cellular localization of human ABC-transporters have been gained. Here we review novel lipidomic technologies including quantitative mRNA expression monitoring by realtime RT-PCR and DNA-microarrays, lipid mass spectrometry, cellular fluorescence imaging and flow cytometry as promising tools to further define regulatory networks, lipid species patterns and subcellular domains important for ABC-transporter-mediated lipid trafficking.

ATP-Binding Cassette Transporters↗

PubMed2004

Expression analysis of ABC transporters reveals differential functions of tandemly duplicated genes in Caenorhabditis elegans.

We have previously identified 60 predicted ABC transporter genes in the Caenorhabditis elegans genome and classified them into eight groups. As an initial step towards understanding how these putative ABC genes work in worms, we generated promoter-fluorescent protein fusions for the entire family to address when and where these genes are turned on in vivo. Both Aequoria green fluorescent protein (GFP) and Discosoma red fluorescent protein (RFP) were used as reporters in our transgenic assay. Observable expression is more frequently seen from fusions to genes in subfamilies B, C, D and E than those in subfamilies A and G. Sixteen worm ABC genes are found in tandem duplications, forming two four-gene clusters and four two-gene clusters. Fifteen out of the 16 duplicated gene promoters drove different or partially overlapping expression patterns, suggesting active functions for these duplicated genes. Furthermore, our results suggest that an internal promoter can cause differential expression of genes within an operon. Finally, our observations suggest that it is possible for coding sequences to function as a regulatory region for a neighbouring gene.

ATP-Binding Cassette Transporters↗

PubMed2006

Distinct structural and functional properties of the ATPase sites in an asymmetric ABC transporter.

The ABC transporter associated with antigen processing (TAP) shuttles cytosolic peptides into the endoplasmic reticulum for loading onto class I MHC molecules. Transport is fueled by ATP binding and hydrolysis at two distinct cytosolic ATPase sites. One site comprises consensus motifs shared among most ABC transporters, while the second has substituted, degenerate motifs. Biochemical and crystallography experiments with a TAP cytosolic domain demonstrate that the consensus ATPase site has high catalytic activity and facilitates ATP-dependent dimerization of the cytosolic domains, which is an important conformational change during transport. In contrast, the degenerate site is defective in dimerization and ATP hydrolysis. Full-length TAP mutagenesis demonstrates the necessity for at least one consensus site, supporting our conclusion that the consensus site is the principal facilitator of substrate transport. Since asymmetry of the ATPase site motifs is a feature of many mammalian homologs, our proposed model has broad implications for ABC transporters.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

The gene family of ABC transporters--novel mutations, new phenotypes.

Members of the ABC (ATP-binding cassette) superfamily of genes encode transmembrane proteins that are involved in the transport of a variety of substrates both in and out of the cells, in addition to across intracellular membranes. Recently, mutations in two ABC-transporter genes, ABCC6 and ABCA12, have been demonstrated to underlie phenotypically different diseases affecting the skin (pseudoxanthoma elasticum and harlequin ichthyosis, respectively), attesting to the spectrum of ABC gene mutations in human diseases. These findings have a major impact on the molecular genetics of these devastating disorders in terms of DNA-based prenatal testing and pre-implantation genetic diagnosis.

ATP-Binding Cassette Transporters↗