Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pleiotropic drug resistance (PDR) in the yeast Saccharomyces cerevisiae can arise from overexpression of ATP-binding cassette (ABC) efflux pumps such as Pdr5 and Snq2. Mutations in the transcription factor genes PDR1 and PDR3 are also associated with PDR. We show here that a pdr1-3 mutant exhibits a PDR phenotype, including elevated resistance to the mutagen 4-nitroquinoline-N-oxide, a known substrate for Snq2 but not for Pdr5. Northern analysis and immunoblotting demonstrated that the SNQ2 gene is 10-fold overexpressed in a pdr1-3 gain-of-function mutant strain, whereas Snq2 expression is severely reduced in a delta pdr1 deletion strain, and almost abolished in a delta pdr1 delta pdr3 double disruptant when compared to the PDR1 strain. However, expression of the Ste6 a-factor pheromone transporter, another yeast ABC transporter not associated with PDR, is unaffected in pdr1-3 mutant cells and in strains carrying delta pdr1, delta pdr3, or delta pdr1 delta pdr3 deletions. Finally, DNA footprint analysis revealed that the SNQ2 promoter contains three binding sites for Pdr3. Our results identify SNQ2 as a novel target for both Pdr1 and Pdr3, and demonstrate that the PDR phenotype of a pdr1-3 mutant strain results from overexpression of more than one ABC drug-efflux pump.
Mol Microbiol 1996 Apr
PMID:The ATP-binding cassette multidrug transporter Snq2 of Saccharomyces cerevisiae: a novel target for the transcription factors Pdr1 and Pdr3. 886 Dec 9

As an approach to characterizing all human ATP-binding cassette (ABC) superfamily genes, a search of the human expressed sequence tag (EST) database was performed using sequences from known ABC genes. A total of 105 clones, containing sequences of potential ABC genes, were identified, representing 21 distinct genes. This brings the total number of characterized human ABC genes from 12 to 33. The new ABC genes were mapped by PCR on somatic cell and radiation hybrid panels and yeast artificial chromosomes (YACs). The genes are located on human chromosomes 1, 2, 3, 4, 6, 7, 10, 12, 13, 14, 16, 17 and X; at locations distinct from previously mapped members of the superfamily. The characterized genes display extensive diversity in sequence and expression pattern and this information was utilized to determine potential structural, functional and evolutionary relationships to previously characterized members of the ABC superfamily.
Hum Mol Genet 1996 Oct
PMID:Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. 889 2

Closure of ATP-sensitive potassium channels in pancreatic islet beta-cells initiates a cascade of events that leads to insulin secretion. beta-Cell ATP-sensitive potassium currents can be reconstituted by coexpression of the inward rectifier Kir6.2 and the sulfonylurea receptor (SUR), a member of the ATP-binding cassette superfamily. Mutations in SUR have been identified in individuals affected with familial persistent hyper-insulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder of glucose metabolism which is linked to chromosome 11p15.1 and characterized by unregulated secretion of insulin and profound hypoglycemia. Because the Kir6.2 locus is within 5 kilobases (kb) of the SUR gene on chromosome 11p15.1 and it is a necessary member of the beta-cell KATP channel, we considered Kir6.2 as a candidate gene for PHHL we identified a homozygous point mutation in Kir6.2 in the genomic DNA of a child, severely affected with PHHI, from a consanguineous family. This mutation is predicted to disrupt the conserved alpha-helical second transmembrane (M2) domain of the inward rectifier by substitution of a proline for a leucine residue (L147P). Mutation of Kir6.2, like SUR, appears to lead to the PHHI phenotype suggesting that Kir6.2 is necessary, although not sufficient, for normal regulation of insulin release.
Hum Mol Genet 1996 Nov
PMID:Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. 892 10

The Serratia marcescens haemophore HasA is secreted by an ABC exporter comprising three envelope proteins. The ABC protein (ATP-binding cassette) HasD and the MFP protein (membrane fusion protein) HasE but not the outer membrane component have been isolated previously. In Escherichia coli, TolC, the outer membrane component of the haemolysin transporter, can form a hybrid exporter with HasD and HasE. This hybrid secretes HasA and the very similar metalloproteases from S. marcescens and Erwinia chrysanthemi. By analogy, the genuine exporter was predicted to secrete metalloproteases. The hasF gene was thus cloned from S. marcescens into an E. coli tolC mutant carrying hasD and hasE genes, by screening for a proteolytic phenotype on skimmed-milk plates. hasF encodes a protein sharing 74% identity with the E. coli TolC protein. Anti-TolC antibodies cross-reacted with a protein with an apparent molecular weight of 53 kDa in E. coli expressing hasF and in S. marcescens. hasF is unlinked to the has cluster and, unlike the has operon, is not iron regulated. hasF complements some of the tolC phenotypes, including drug- and detergent sensitivities and haemolysin secretion but not colicin E1 uptake. This suggests that the various functions of TolC could correspond to distinct domains on the protein.
Mol Microbiol 1996 Oct
PMID:Cloning of the Serratia marcescens hasF gene encoding the Has ABC exporter outer membrane component: a TolC analogue. 893 Sep 11

Morphological differentiation in the filamentous bacterium Streptomyces coelicolor is believed to involve a mechanism of extracellular signalling that culminates with the formation of an aerial mycelium. We have identified a gene cluster designated bldK in which insertional and deletion mutations cause a block in aerial mycelium formation. Extracellular complementation experiments indicate that bldK defines a step in a cascade of extracellular signals; colonies of a bldK-mutant strain extracellularly complement bld261-mutant colonies, and are themselves extracellularly complemented by bldA- and bldH-mutant colonies. The bldK locus, which is located at 5 o'clock on the genetic map and within Asel fragment "N' on the physical map, consists of five adjacent open reading frames. These genes specify homologues of the subunits of the oligopeptide-permease family of ATP-binding cassette (ABC) membrane-spanning transporters. Because bldK mutations confer resistance to the toxic tripeptide bialaphos, it is inferred that BldK is an oligopeptide importer. We propose that the BldK transporter is responsible for the import of an extracellular signalling molecule produced under the control of the wild-type product of the bld261 gene. The BldK-imported signal, in turn, causes the production of a second extracellular signal molecule that depends on the products of bldA and bldH for its action.
Mol Microbiol 1996 Dec
PMID:An oligopeptide permease responsible for the import of an extracellular signal governing aerial mycelium formation in Streptomyces coelicolor. 897 10

We have cloned, sequenced and characterized a gene from Trypanosoma cruzi (Y strain), termed tcpgp2, which encodes a member of the ABC (ATP-binding cassette) superfamily of evolutionarily conserved transport proteins. The nucleotide sequence of the tcpgp2 gene was determined. It presents a 4602-bp open reading frame, coding for a 1534-amino acid protein, with a predicted molecular mass of 169,470 Da. The deduced amino acid sequence of tcpgp2 exhibited a remarkable homology with the P-glycoprotein-related genes of Leishmania tarentolae, the yeast cadmium factor (YCF1) and the human multidrug resistance-associated protein (MRP). Southern blot analysis using a specific probe indicated that the Tcpgp2 P-glycoprotein is encoded by a single copy gene which maps to a chromosome of about 900 kb. Northern blot analysis revealed that tcpgp2 gene is expressed as a polyadenylated transcript of approximately 5 kb in dividing amastigote and epimastigote forms; we did not detect the transcript in the non-dividing trypomastigote forms of the parasite. Gene transfection experiments in Leishmania tropica indicated that, under the conditions tested, tcpgp2 gene is not involved in drug resistance.
Mol Biochem Parasitol 1996 Jan
PMID:Molecular characterization of a P-glycoprotein-related tcpgp2 gene in Trypanosoma cruzi. 899 13

The genetic mechanisms underlying cisplatin (DDP) resistance in yeast were investigated by examining the cytotoxicity of DDP to Schizosaccharomyces pombe mutants that were either hypersensitive or resistant to Cd. Despite reports that have linked glutathione (GSH) to DDP resistance in human cancer cells, we found that a mutant of S. pombe that was hypersensitive to Cd by virtue of a 15-fold reduction in GSH level and lack of phytochelatin production was as tolerant as the wild-type strain to DDP. A mutant that harbored a mutation in hmt1, the gene encoding an ATP-binding cassette-type transporter for vacuolar sequestration of a phytochelatin/Cd complex, exhibited only mild hypersensitivity to DDP even though it was 100-fold more sensitive to Cd. Overexpression of hmt1 in wild-type or mutant cells conferred tolerance to Cd but failed to do the same for DDP. However, a strain that produced 6-fold more sulfide than wild-type cells was found to be 6-fold more resistant to DDP and twice as resistant to Cd; an association between DDP resistance and sulfide production was observed in three other strains that were examined, and overproduction of sulfide was accompanied by reduced platination of DNA. These results indicate that GSH and the GSH-derived phytochelatin peptides do not play critical roles in determining sensitivity to DDP in S. pombe but rather identify increased production of sulfide as a possible new mechanism of DDP resistance that may also be relevant to human cells.
Mol Pharmacol 1997 Jan
PMID:Role of determinants of cadmium sensitivity in the tolerance of Schizosaccharomyces pombe to cisplatin. 901 41

We have recently described the mpr gene of Mycobacterium smegmatis whose product confers resistance to mycobacteriophages L5 and D29 when overproduced (Barsom and Hatfull (1996) Mol. Microbiol. 21, 159-170). We have determined the nt sequence of approximately 3.5 kb immediately adjacent to mpr which appears to encode components of an ATP-binding cassette (ABC) transport system. Four closely-spaced open reading frames (ORF) were identified although two of these may cooperate to produce an integral membrane component of the transport system via a programmed translational frameshift. Another putative protein is also predicted to be an integral membrane protein, while the third is an ABC-transporter protein. We propose that these three putative proteins form a mycobacterial membrane-bound complex involved in protein-dependent transport. This is the first ABC-transport system to be described in mycobacteria.
 ...
PMID:A putative ABC-transport operon of Mycobacterium smegmatis. 903 23

A transposition mutant of Bacillus subtilis (designated JC901) that was isolated on the basis of growth inhibition by Na+ at elevated pH, was deficient in energy-dependent Na+ extrusion. The capacity of the mutant JC901 for Na(+)-dependent pH homeostasis was unaffected relative to the wild-type strain, as assessed by regulation of cytoplasmic pH after an alkaline shift. The site of transposition was near the 3'-terminal end of a gene, natB, predicted to encode a membrane protein, NatB. NatB possesses six putative membrane-spanning regions at its C-terminus, and exhibits modest sequence similarity to regions of eukaryotic Na+/H+ exchangers. Sequence and Northern blot analyses suggested that natB forms an operon with an upstream gene, natA. The predicted product of natA is a member of the family of ATP-binding proteins that are components of transport systems of the ATP-binding cassette (ABC) or traffic ATPase type. Expression of the lacZ gene that was under control of the promoter for natB indicated that expression of the operon was induced by ethanol and the protonophore carbonylcyanide p-chlorophenylhydrazone (CCCP), and more modestly, by Na+, and K+, but not by choline or a high concentration of sucrose. Restoration of the natAB genes, cloned in a recombinant plasmid (pJY1), complemented the Na(+)-sensitive phenotype of the mutant JC901 at elevated pH and significantly increased the resistance of the mutant to growth inhibition by ethanol and CCCP at pH 7; ethanol was not excluded, however, from the cells expressing natAB, so ethanol-resistance does not result from NatAB-dependent ethanol efflux. Transformation of the mutant with pJY1 did markedly enhance the capacity for Na+ efflux, which was further stimulated by CCCP. In the absence of CCCP, NatAB-mediated Na+ efflux was stimulated by K+. Concomitant NatAB-dependent K+ uptake occurred, as monitored by 86Rb+ uptake; this uptake was inhibited by CCCP and is thus secondary to the primary, electrogenic Na+ efflux. A B. subtilis mutant strain (BsAJ96) in which most of natA and all of natB was replaced by a spectinomycin-resistance-gene cassette exhibited phenotypic properties identical to JC901 Under anaerobic conditions, using a strain of B. subtilis deleted in atp genes encoding the F1F0-ATPase (BD99-A), glucose energized Na+ exclusion in an arsenate-sensitive manner; this exclusion capacity was absent in a strain deleted both in atp and natAB genes (BsAJ96-A). We conclude that NatAB is an inducible, ABC transport system that catalyses ATP-dependent electrogenic Na+ extrusion without mechanistically coupled proton or K+ uptake. This is a novel mode of Na+ extrusion that is hypothesized to play an inducible role in exclusion of cytotoxic Na+ and in the secondary stimulation of K+ uptake, especially when the function of the membrane as an ion-permeability barrier is compromised by agents such as alcohols or uncouplers.
Mol Microbiol 1997 Mar
PMID:A two-gene ABC-type transport system that extrudes Na+ in Bacillus subtilis is induced by ethanol or protonophore. 910 3

Many non-lantibiotic bacteriocins of lactic acid bacteria are produced as precursors which have N-terminal leader peptides that share similarities in amino acid sequence and contain a conserved processing site of two glycine residues in positions -1 and -2. A dedicated ATP-binding cassette (ABC) transporter is responsible for the proteolytic cleavage of the leader peptides and subsequent translocation of the bacteriocins across the cytoplasmic membrane. To investigate the role that these leader peptides play in the recognition of the precursor by the ABC transporters, the leader peptides of leucocin A, lactococcin A or colicin V were fused to divergicin A, a bacteriocin from Carnobacterium divergens that is secreted via the cell's general secretion pathway. Production of divergicin was monitored when these fusion constructs were introduced into Leuconostoc gelidum, Lactococcus lactis and Escherichia coli, which carry the secretion apparatus for leucocin A, lactococcins A and B, and colicin V, respectively. The different leader peptides directed the production of divergicin in the homologous hosts. In some cases production of divergicin was also observed when the leader peptides were used in heterologous hosts. For ABC-transporter-dependent secretion in E. coli the outer membrane protein TolC was required. Using this strategy, colicin V was produced in L. lactis by fusing this bacteriocin behind the leader peptide of leucocin A.
Mol Microbiol 1997 Mar
PMID:Double-glycine-type leader peptides direct secretion of bacteriocins by ABC transporters: colicin V secretion in Lactococcus lactis. 910 19


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