Cyclophilin-dependent stimulation of transcription by cyclosporin A.
Exposure to cyclosporin A (CspA) increased laccase (lac-1) transcript accumulation in the chestnut blight fungus Cryphonectria parasitica. This response was suppressed by compounds that interfere with calcium-dependent signal transduction and by the presence of a virulence-attenuating mycovirus. CspA stimulated the accumulation of mRNA from a nonhomologous reporter fused to the lac-1 promoter, indicating that the increased transcript levels resulted from an increase in promoter activity. Based on the current model for the regulation of lac-1 transcription, these results suggest that CspA interferes with a negative regulatory pathway that normally constrains lac-1 promoter activity. Significantly, CspA did not stimulate lac-1 transcription in mutant strains deficient in CspA binding activity, directly demonstrating a requirement for the interaction of CspA and cyclophilin in the modulation of lac-1 transcription. Our results establish that CspA treatment can stimulate gene transcription and that cyclophilin is the cellular receptor that mediates this activity.
Larson
T G
TG
Molecular Oncology and Virology, Roche Institute of Molecular Biology, Roche Research Center, Nutley, NJ 07110.
Nuss
D L
DL
D000591:Amino Acid Isomerases / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004352:Drug Resistance, Microbial / Q000235:genetics / Q000528:radiation effects; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005800:Genes, Fungal; D042845:Laccase; D016296:Mutagenesis; D009355:Neomycin / Q000494:pharmacology; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014466:Ultraviolet Rays; D013098:Xylariales / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*
D002352:Carrier Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D004533:Egtazic Acid; D016572:Cyclosporine; D003513:Cycloheximide; D010088:Oxidoreductases; D042845:Laccase; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D009355:Neomycin; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid