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PubMed1998

Proteoglycans in the nucleus pulposus of canine intervertebral discs after chondroitinase ABC treatment.

Experimental chemonucleolysis of the canine intervertebral disc with chondroitinase ABC and chymopapain was compared during a 52-week period. Roentgenograms and magnetic resonance imaging were used to examine changes in disc space and water content, respectively. Disc space narrowing and reductions in disc water content after chondroitinase ABC treatment were less than that after chymopapain. High-performance liquid chromatography was performed to measure changes in proteoglycans. Similarly to chymopapain, chondroitinase ABC degrades proteoglycans in the nucleus pulposus and decreases their quantity. However, large differences in the molecular weight and acidity of the resynthesized proteoglycans and in the chain length of the resynthesized glycosaminoglycans were observed between the two enzymes. The difference in disc space narrowing and the changes in disc water content between the two enzymes might result from differences in the characteristics of the resynthesized proteoglycans.

Acids↗

PubMed1999

Interferon-gamma-induced ICAM-1 and CD40 expression, complete lack of HLA-DR and CD80 (B7.1), and inconsistent HLA-ABC expression in basal cell carcinoma: a possible role for interleukin-10?

Basal cell carcinomas (BCCs) of the skin show varying degrees of peritumoural inflammatory infiltrate consisting mainly of T cells, but lack an effective T-cell-mediated immune response. This may be caused by the absence of the major histocompatibility complex (MHC) class I and II antigens, intercellular adhesion molecule-1 (ICAM-1), CD40 and CD80 (B7.1). Interferon-gamma (IFN-gamma) is known to induce or up-regulate their expression on epithelial cells, whereas interleukin-10 (IL-10) down-regulates their expression. The induction and up-regulation of HLA-ABC, HLA-DR, ICAM-1, CD40, and CD80 in BCC and normal skin from BCC patients were investigated in a culture system using recombinant human IFN-gamma (rHuIFN-gamma). The levels of IL-10 were determined in the supernatants after culture. The results showed that only ICAM-1 expression was significantly up-regulated on BCC cells. However, in the normal epidermis of BCC patients and in the epidermis overlying the tumour nests, significant up-regulation of ICAM-1, and CD40, and CD80 and slight up-regulation of HLA-DR were observed. No changes in HLA-ABC expression were observed in either normal skin or BCC. High levels of IL-10 were present in the supernatants of BCC biopsies after culture. It may be concluded that it is highly likely that the presence of IL-10 in BCC is directly or indirectly responsible for the complete lack of expression of HLA-DR, ICAM-1, CD40 and CD80 and the inconsistent expression of HLA-ABC on BCC cells in situ and may be a way of escaping immune survillance.

Adult↗

PubMed1998

Factor analyses of WISC-R and K-ABC in a Dutch sample of children referred for learning disabilities.

This study examined correlations between WISC-R and K-ABC subtests in a sample of 101 children referred for learning disabilities. A considerable overlap between the two instruments was found. Separate factor analyses of the WISC-R and K-ABC were conducted. By and large, the WISC-R factor structure was similar to that found for standardization samples. Three factors emerged, namely Verbal Comprehension, Perceptual Organization, and Freedom From Distractibility. In line with earlier findings, the K-ABC factor analysis resulted in two factors: Simultaneous and Sequential Processing. A shorter battery combining subtests from both instruments is discussed.

Adolescent↗

PubMed2004

Selective formation of AAB- and ABC-type heterotrimeric alpha-helical coiled coils.

The alpha-helical coiled coils have a representative amino acid sequence of (abcdefg)(n) heptad repeats. We previously reported that two peptides named IZ-2A and IZ-2W formed an (IZ-2A)(2)/IZ-2W heterotrimer with an Ala-Ala-Trp interaction in the hydrophobic core. In this paper, we describe the selective formation of AAB- and ABC-type heterotrimers. To increase the selectivity of the AAB-type heterotrimeric formation, Lys residues at the f position were mutated to either an Ala or a Gln residue to form IZ-2A(fA) or IZ-2W(fQ). Separately, both IZ-2A(fA) and IZ-2W(fQ) have a random structure at pH 7 and 20 degrees C. However, together IZ-2A(fA) and IZ-2W(fQ) form a 2:1 complex with a thermal transition midpoint (Tm) of 48 degrees C. This procedure was applied to prepare the ABC-type heterotrimer, in which two sets of Ala-Ala-Trp interactions were designed in the hydrophobic core. Interhelical interaction between the e and g positions and the alpha-helical propensity of the amino acid at the f position were also considered in the design. The resultant three peptides selectively formed the ABC-type heterotrimer with a Tm of 51 degrees C. Other peptide combinations had random coil properties.

Amino Acid Sequence↗

PubMed2002

Single-cell image analysis to assess ABC-transporter-mediated efflux in highly purified hematopoietic progenitors.

BACKGROUND: Normal and malignant hematopoietic stem cells are characterized by their capacity to actively extrude fluorescent dyes. The contribution of different ATP-binding cassette (ABC) transporters to this phenomenon is largely unknown due to the small stem cell numbers limiting the use of standard methods to assess functional efflux. METHODS: We used epifluorescence microscopy (EFM) in combination with single-cell image analysis to study ABC-transporter-mediated efflux in highly purified, viable, CD34+CD38- cells sorted on an adhesive biolayer. P-glycoprotein and multidrug-resistant protein (MRP)-mediated efflux were quantitated using fluorescent substrates (rhodamine-123 and calcein acetoxymethyl ester [calcein-AM]) and specific inhibitors (verapamil and probenecid, respectively). RESULTS: The feasibility, sensitivity, and reproducibility of rhodamine-123 efflux quantitation using single-cell EFM was shown in cell lines and compared with standard flow cytometric assessment. P-glycoprotein-mediated transport was higher in CD34+CD38- cells than in more differentiated progenitors (mean efflux index = 2.24 +/- 0.35 and 1.14 +/- 0.11, respectively; P = 0.01). P-glycoprotein-mediated transport was the main determinant of the rhodamine "dull" phenotype of these cells. In addition, significant MRP-mediated efflux was demonstrated in CD34+CD38- and CD38+ cells (mean efflux index = 1.42 +/- 0.19 and 1.28 +/- 0.18, respectively). CONCLUSION: The described method is a valuable tool for assessing ABC-transporter-mediated efflux in highly purified single cells. Both P-glycoprotein and MRP-mediated efflux are present in human CD34+CD38- hematopoietic stem cells.

ADP-ribosyl Cyclase↗

PubMed2003

The ABC-transporter signature motif is required for peptide translocation but not peptide binding by TAP.

The transporter associated with antigen processing (TAP) translocates peptides from their site of generation in the cytosol to the lumen of the endoplasmic reticulum for binding to MHC class I molecules. TAP is a member of the ATP-binding cassette (ABC) transporter family whose members utilize energy from ATP hydrolysis to translocate substrates across membranes. The highly conserved nucleotide-binding domains of ABC transporters couple ATP hydrolysis to substrate translocation by the membrane domains. The conserved 'signature motif' can be identified in the nucleotide-binding domains of all ABC transporters, and may play a role in ATP hydrolysis. Here we show that introduction of mutations into the signature motifs of either TAP1 or TAP2 inhibits the translocation of peptide without affecting binding of either peptide or ATP by TAP. We therefore conclude that the signature motifs in both TAP1 and TAP2 are required after peptide binding to facilitate peptide translocation by TAP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1989

Effects of chondroitinase-ABC on proteoglycans and swelling properties of fibrocartilage in bovine flexor tendon.

Fibrocartilaginous regions of bovine deep flexor tendon were treated with chondroitinase-ABC and trypsin in order to extract proteoglycans from the extracellular matrix and thereby investigate the contribution of proteoglycan and collagen organization to tissue material properties. Chondroitinase-ABC digestion of tendon specimens for 24 h resulted in extraction of 60% of tissue glycosaminoglycan and leaching of the degraded large proteoglycan from the tissue residue. The totally degraded core protein of the small dermatan sulfate proteoglycan remained with the tissue residue, indicating that it is specifically associated with the tissue residue and that this association is not dependent on the glycosaminoglycan chains. Treatment of residues with trypsin after chondroitinase-ABC digestion depleted the specimens of proteoglycan. Bulk swelling tests on enzyme-extracted specimens showed that the distinct swelling properties of the fibrocartilaginous regions of the distal flexor tendon could be partially accounted for by elevated levels of proteoglycan. Swelling tests also showed that the distinct collagen organization of this region contributes significantly to the tissue's material properties. These results suggest that the fibrocartilaginous organization and composition of the articulating layer of distal tendon are adapted for mechanical requirements unique to this site, which receives compressive and frictional loads in addition to tensile loads.

Animals↗

PubMed2004

Asymmetric ABC-triblock copolymer membranes induce a directed insertion of membrane proteins.

Asymmetric molecules and materials provide an important basis for the organization and function of biological systems. It is well known that, for example, the inner and outer leaflets of biological membranes are strictly asymmetric with respect to lipid composition and distribution. This plays a crucial role for many membrane-related processes like carrier-mediated transport or insertion and orientation of integral membrane proteins. Most artificial membrane systems are, however, symmetric with respect to their midplane and membrane proteins are incorporated with random orientation. Here we describe a new approach to induce a directed insertion of membrane proteins into asymmetric membranes formed by amphiphilic ABC triblock copolymers with two chemically different water-soluble blocks A and C. In a comparative study we have reconstituted His-tag labeled Aquaporin 0 in lipid, ABA block copolymer, and ABC block copolymer vesicles. Immunolabeling, colorimetric, and fluorescence studies clearly show that a preferential orientation of the protein is only observed in the asymmetric ABC triblock copolymer membranes.

Aquaporins↗

PubMed2006

An important role of a "probable ATP-binding component of ABC transporter" during the process of Pseudomonas aeruginosa resistance to fluoroquinolone.

In order to find new drug target to eliminate the fluoroquinolone resistance, the in vitro progress of Pseudomonas aeruginosa fluoroquinolone resistance was mimicked, and then proteomic analysis was applied to comparing different protein profiles during the resistant process. The results show that the expression of a "probable ATP-binding component of ATP binding cassette (ABC) transporter" existed in ciprofloxacin-intermediate and -resistant strains, but not in sensitive strain. In addition, the ciprofloxacin concentrations in P. aeruginosa strains, which were obtained from the progress of P. aeruginosa fluoroquinolone resistance, were determined by means of HPLC; the results show that the decrease of the intracellular concentration of drug and the expression of this new protein nearly take place simultaneously. The changes of mRNA levels of the probable ATP-binding component of ABC transporter were detected by virtue of RT-PCR and showed that this protein did not express in the sensitive strains but expressed increasingly in the intermediate and resistant strains. In order to determine the relationships between the development of antibiotic resistance and this protein further, a DNAzyme was designed to aim at the mRNA of the probable ATP-binding component of ABC transporter directly; the ciprofloxacin resistance of P. aeruginosa was partially reduced in vivo by inhibiting the expression of this protein. This DNAzyme has no effect on sensitive strain. And the comparison of drug intracellular concentrations between DNAzyme-treated strains and its control strains shows that this protein may be included in the course of active drug efflux.

ATP-Binding Cassette Transporters↗

PubMed1992

A new subfamily of bacterial ABC-type transport systems catalyzing export of drugs and carbohydrates.

Sequence comparison studies revealed that the drug resistance transporter of Streptomyces peucetius (DrrAB) and two nodulation gene products (NodIJ) of Rhizobium leguminosarum are homologous to proteins encoded by three sets of genes that comprise capsular polysaccharide export systems in gram-negative bacteria: KpsTM of Escherichia coli, BexABC of Haemophilus influenzae, and CtrDCB of Neisseria meningitidis. These five systems comprise a new subfamily within the family of ATP binding cassette (ABC)-type transporters. We have termed this subfamily the ABC-2 subfamily. For three of the systems comprising this subfamily (Drr, Nod, and Kps) only one integral membrane constituent has been identified, whereas for the other two systems (Bex and Ctr) two dis-similar integral membrane constituents have been found. This observation suggests that the transmembrane channels of ABC-2-type transporters can be formed of homo- or heterooligomers as is true of several other classes of transport systems.

Adenosine Triphosphate↗

PubMed2002

ABC transporters as phenotypic markers and functional regulators of stem cells.

Characterization of molecules with tightly controlled expression patterns during differentiation represents an approach to understanding regulation of hematopoietic stem cell commitment. The multidrug resistance-1 (MDR1) gene product, P-glycoprotein, and the breast cancer resistance protein (BCRP) are expressed differentially during hematopoiesis, with the highest levels in primitive bone marrow stem cell populations that are CD34(low) and CD34(-), respectively. Roles for ATP-binding cassette (ABC) transporter superfamily members in conferring drug resistance have been extensively described. However, recent hematopoietic overexpression studies have begun to reveal previously unknown roles for ABC transporter function in normal and malignant hematopoiesis. Expression of MDR1 and BCRP transporters in the myeloid lineage has been reported in blasts from acute myeloid leukemia, but very low to undetectable in normal myelomonocytic cells. Retroviral-mediated dysregulated expression of the MDR1 transporter resulted in increased hematopoietic repopulating activity and myeloproliferative disease in mice. A distinct functional role for the BCRP transporter as a negative regulator of hematopoietic repopulating activity has recently been demonstrated using the same approach. Additionally, the presence of BCRP expression specifically on hematopoietic side-population stem cells and neural stem/progenitors, makes BCRP an attractive candidate marker for isolation of stem cells with the ability to respond to diverse environmental cues. Regulation of stem cell biology by ABC transporters has emerged as an important new field of investigation. In light of these findings, it will be critical to further characterize this family of proteins in hematopoietic lineage-restricted stem cells and in pluripotent stem cells capable of crossing lineage barriers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the peroxisomal assembly protein PEX19p.

Four ABC half transporters (ALDP, ALDRP, PMP70, and PMP69) have been identified in the mammalian peroxisomal membrane but no function has been unambiguously assigned to any of them. To date X-linked adrenoleukodystrophy (X-ALD) is the only human disease known to result from a defect of one of these ABC transporters, ALDP. Using the yeast two-hybrid system and in vitro GST pull-down assays, we identified the peroxin PEX19p as a novel interactor of ALDP, ALDRP, and PMP70. The cytosolic farnesylated protein PEX19p was previously shown to be involved in an early step of the peroxisomal biogenesis. The PEX19p interaction occurs in an internal N-terminal region of ALDP which we verified to be important for proper peroxisomal targeting of this protein. Farnesylated wild-type PEX19p and a farnesylation-deficient mutant PEX19p did not differ in their ability to bind to ALDP. Our data provide evidence that PEX19p is a cytosolic acceptor protein for the peroxisomal ABC transporters ALDP, PMP70, and ALDRP and might be involved in the intracellular sorting and trafficking of these proteins to the peroxisomal membrane.

ATP Binding Cassette Transporter, Subfamily D↗

PubMed2000

The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane.

The products of the ABC gene family can be generally classified as either full-transporters of half-transporters. Full-transporters are expressed in the plasma membrane, whereas half-transporters are usually found in intracellular membranes. Recently, an ABC half-transporter, the ABCG2 gene product Breast Cancer/Mitoxantrone Resistance Protein (BCRP/MXR), has been shown to cause mitoxantrone and topotecan resistance. The purpose of this study was to determine the expression and the intracellular localization of this protein in various drug-resistant cell lines. BCRP/MXR expression was determined by Western blot and immunohistochemistry. This protein is highly overexpressed in several drug-resistant cell lines and localizes predominantly to the plasma membrane, instead of to intracellular membranes as seen with all other known half-transporters. Therefore, BCRP/MXR is unique among the ABC half-transporters by being localized to the plasma membrane.

ATP-Binding Cassette Transporters↗

PubMed2001

Crystal structure of the SMC head domain: an ABC ATPase with 900 residues antiparallel coiled-coil inserted.

SMC (structural maintenance of chromosomes) proteins are large coiled-coil proteins involved in chromosome condensation, sister chromatid cohesion, and DNA double-strand break processing. They share a conserved five-domain architecture with three globular domains separated by two long coiled-coil segments. The coiled-coil segments are antiparallel, bringing the N and C-terminal globular domains together. We have expressed a fusion protein of the N and C-terminal globular domains of Thermotoga maritima SMC in Escherichia coli by replacing the approximately 900 residue coiled-coil and hinge segment with a short peptide linker. The SMC head domain (SMChd) binds and condenses DNA in an ATP-dependent manner. Using selenomethionine-substituted protein and multiple anomalous dispersion phasing, we have solved the crystal structure of the SMChd to 3.1 A resolution. In the monoclinic crystal form, six SMChd molecules form two turns of a helix. The fold of SMChd is closely related to the ATP-binding cassette (ABC) ATPase family of proteins and Rad50, a member of the SMC family involved in DNA double-strand break repair. In SMChd, the ABC ATPase fold is formed by the N and C-terminal domains with the 900 residue coiled-coil and hinge segment inserted in the middle of the fold. The crystal structure of an SMChd confirms that the coiled-coil segments in SMC proteins are anti-parallel and shows how the N and C-terminal domains come together to form an ABC ATPase. Comparison to the structure of the MukB N-terminal domain demonstrates the close relationship between MukB and SMC proteins, and indicates a helix to strand conversion when N and C-terminal parts come together.

Adenosine Triphosphatases↗

PubMed1995

The effect of chondroitinase ABC on rabbit intervertebral disc. Radiological, histological and electron microscopic findings.

Seventy-eight rabbit lumbar discs were evaluated by radiographs and histology after the injection of chondroitinase ABC (40 U/ml for each disc) and compared with injection with phosphate buffer, and also with a control group who were not injected. There was considerable narrowing of the disc space after chondroitinase ABC injection. Safranin-0 depletion was present in the anterior part of the annulus fibrosus near to the nucleus pulposus in all the treated discs, indicating loss of proteoglycan. Electron microscopy showed collapse of the chondrocytes and notochordal cells. These findings suggest that chondroitinase ABC may be another chemonucleolytic agent which decreases disc volume and consequently decompresses the spinal cord or nerve roots; its effects were confined to the tissues within the intervertebral disc.

Animals↗

PubMed2002

Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters.

Cancer cell resistance to chemotherapy is often mediated by overexpression of P-glycoprotein, a plasma membrane ABC (ATP-binding cassette) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. P-glycoprotein (ABCB1, according to the human gene nomenclature committee) consists of two homologous halves each containing a transmembrane domain (TMD) involved in drug binding and efflux, and a cytosolic nucleotide-binding domain (NBD) involved in ATP binding and hydrolysis, with an overall (TMD-NBD)2 domain topology. Homologous ABC multidrug transporters, from the same ABCB family, are found in many species such as Plasmodiumfalciparum and Leishmania spp. protozoa, where they induce resistance to antiparasitic drugs. In yeasts, some ABC transporters involved in resistance to fungicides, such as Saccharomyces cerevisiae Pdr5p and Snq2p, display a different (NBD-TMD)2 domain topology and are classified in another family, ABCG. Much effort has been spent to modulate multidrug resistance in the different species by using specific inhibitors, but generally with little success due to additional cellular targets and/or extrusion of the potential inhibitors. This review shows that due to similarities in function and maybe in three-dimensional organization of the different transporters, common potential modulators have been found. An in vitro 'rational screening' was performed among the large flavonoid family using a four-step procedure: (i) direct binding to purified recombinant cytosolic NBD and/or full-length transporter, (ii) inhibition of ATP hydrolysis and energy-dependent drug interaction with transporter-enriched membranes, (iii) inhibition of cell transporter activity monitored by flow cytometry and (iv) chemosensitization of cell growth. The results indicate that prenylated flavonoids bind with high affinity, and strongly inhibit drug interaction and nucleotide hydrolysis. As such, they constitute promising potential modulators of multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

A transporter of Escherichia coli specific for L- and D-methionine is the prototype for a new family within the ABC superfamily.

An ABC-type transporter in Escherichia coli that transports both L- and D-methionine, but not other natural amino acids, was identified. This system is the first functionally characterized member of a novel family of bacterial permeases within the ABC superfamily. This family was designated the methionine uptake transporter (MUT) family (TC #3.A.1.23). The proteins that comprise the transporters of this family were analyzed phylogenetically, revealing the probable existence of several sequence-divergent primordial paralogues, no more than two of which have been transmitted to any currently sequenced organism. In addition, MetJ, the pleiotropic methionine repressor protein, was shown to negatively control expression of the operon encoding the ABC-type methionine uptake system. The identification of MetJ binding sites (in gram-negative bacteria) or S-boxes (in gram-positive bacteria) in the promoter regions of several MUT transporter-encoding operons suggests that many MUT family members transport organic sulfur compounds.

ATP-Binding Cassette Transporters↗

PubMed2002

The plant PDR family of ABC transporters.

The plant pleiotropic drug resistance (PDR) family of ATP-binding cassette (ABC) transporters has been implicated in the transport of antifungal agents. In this paper, we provide an analysis of the entire family of PDR genes present in the Arabidopsis thaliana (L.) Heynh. genome. This analysis both resolves discrepancies in published inventories of plant ABC proteins and provides an expression analysis of all the annotated Arabidopsis PDR genes. The results indicate that the Arabidopsis genome contains 15 genes encoding PDR proteins and that these genes show a spectrum of specific expression patterns, both at the organ level and in response to various hormonal, environmental and chemical factors. These data provide a scaffold for the future molecular genetic analysis of this important family of ABC transporters. In addition, we demonstrate the usefulness of such data by using them to identify an Arabidopsis PDR protein that may play a role in the extrusion of the antifungal diterpene sclareol. Electronic Supplementary Material is available if you access this article at http://dx.doi.org/10.1007/s00425-002-0889-z. On that page (frame on the left side), a link takes you directly to the supplementary material.

2,4-Dichlorophenoxyacetic Acid↗