Linked Life Data

7530227

Source:http://linkedlifedata.com/resource/pubmed/id/7530227

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-2
pubmed:dateCreated
1995-2-22
pubmed:databankReference
pubmed:abstractText
FK506 and cyclosporin A (CsA) are potent immunosuppressive agents that display antifungal activity. They act by blocking a Ca(2+)-dependent signal transduction pathway leading to interleukin-2 transcription. Each drug forms a complex with its cognate cytosolic immunophilin receptor (i.e., FKBP12-FK506 and cyclophilin-CsA) which acts to inhibit the Ca2+/calmodulin-dependent protein phosphatase 2B, or calcineurin (CN). We and others have defined the Saccharomyces cerevisiae FKS1 gene by recessive mutations resulting in 100-1000-fold hypersensitivity to FK506 and CsA (as compared to wild type), but which do not affect sensitivity to a variety of other antifungal drugs. The fks1 mutant also exhibits a slow-growth phenotype that can be partially alleviated by exogenously added Ca2+ [Parent et al., J. Gen. Microbiol. 139 (1993) 2973-2984]. We have cloned FKS1 by complementation of the drug-hypersensitive phenotype. It contains a long open reading frame encoding a novel 1876-amino-acid (215 kDa) protein which shows no similarity to CN or to other protein phosphatases. The FKS1 protein is predicted to contain 10 to 12 transmembrane domains with a structure resembling integral membrane transporter proteins. Genomic disruption experiments indicate that FKS1 encodes a nonessential function; fks1::LEU2 cells exhibit the same growth and recessive drug-hypersensitive phenotypes observed in the original fks1 mutants. Furthermore, the fks1::LEU2 allele is synthetically lethal in combination with disruptions of both of the nonessential genes encoding the alternative forms of the catalytic A subunit of CN (CNA1 and CNA2). These data suggest that FKS1 provides a unique cellular function which, when absent, increases FK506 and CsA sensitivity by making the CNs (or a CN-dependent function) essential.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0378-1119
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
151
pubmed:geneSymbol
FKS1
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
61-71
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:7530227-Amino Acid Sequence, pubmed-meshheading:7530227-Base Sequence, pubmed-meshheading:7530227-Calcineurin, pubmed-meshheading:7530227-Calmodulin-Binding Proteins, pubmed-meshheading:7530227-Chromosome Mapping, pubmed-meshheading:7530227-Chromosomes, Fungal, pubmed-meshheading:7530227-Cloning, Molecular, pubmed-meshheading:7530227-Cyclosporine, pubmed-meshheading:7530227-DNA Primers, pubmed-meshheading:7530227-Dose-Response Relationship, Drug, pubmed-meshheading:7530227-Echinocandins, pubmed-meshheading:7530227-Fungal Proteins, pubmed-meshheading:7530227-Genes, Fungal, pubmed-meshheading:7530227-Genotype, pubmed-meshheading:7530227-Glucosyltransferases, pubmed-meshheading:7530227-Membrane Proteins, pubmed-meshheading:7530227-Microbial Sensitivity Tests, pubmed-meshheading:7530227-Molecular Sequence Data, pubmed-meshheading:7530227-Phosphoprotein Phosphatases, pubmed-meshheading:7530227-Polymerase Chain Reaction, pubmed-meshheading:7530227-Protein Structure, Secondary, pubmed-meshheading:7530227-Restriction Mapping, pubmed-meshheading:7530227-Saccharomyces cerevisiae, pubmed-meshheading:7530227-Saccharomyces cerevisiae Proteins, pubmed-meshheading:7530227-Tacrolimus
pubmed:year
1994
pubmed:articleTitle
The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growth.
pubmed:affiliation
Department of Biomolecular Disovery, SmithKline Beecham Pharmaceuticals King of Prussia, PA 19406.
pubmed:publicationType
Journal Article, Comparative Study