Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Saccharomyces cerevisiae, 3-amino-1,2,4-triazole (aminotriazole) competitively inhibits the activity of imidazoleglycerolphosphate dehydratase, the product of the HIS3 gene. Wild-type strains are able to grow in the presence of 10 mM aminotriazole because they induce the level of imidazoleglycerolphosphate dehydratase. However, strains containing gcn4 mutations are unable to grow in medium containing aminotriazole because they lack the GCN4 transcriptional activator protein necessary for the coordinate induction of HIS3 and other amino acid biosynthetic genes. Here, we isolated a new gene, designated ATR1, which when present in multiple copies per cell allowed gcn4 mutant strains to grow in the presence of aminotriazole. In wild-type strains, multiple copies of ATR1 permitted growth at extremely high concentrations of aminotriazole (80 mM), whereas a chromosomal deletion of ATR1 caused growth inhibition at very low concentrations (5 mM). When radioactive aminotriazole was added exogenously, cells with multiple copies of ATR1 accumulated less aminotriazole than wild-type cells, whereas cells with the atr1 deletion mutation retained more aminotriazole. Unlike the mammalian mdr or yeast PDR genes that confer resistance to many drugs, ATR1 appears to confer resistance only to aminotriazole. Genetic analysis, mRNA mapping, and DNA sequencing revealed that (i) the primary translation product of ATR1 contains 547 amino acids, (ii) ATR1 transcription is induced by aminotriazole, and (iii) the ATR1 promoter region contains a binding site for the GCN4 activator protein. The deduced amino acid sequence suggests that ATR1 protein is very hydrophobic with many membrane-spanning regions, has several potential glycosylation sites, and may contain an ATP-binding site. We suggest that ATR1 encodes a membrane-associated component of the machinery responsible for pumping aminotriazole (and possibly other toxic compounds) out of the cell.
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PMID:ATR1, a Saccharomyces cerevisiae gene encoding a transmembrane protein required for aminotriazole resistance. 328 Sep 70

Candida glabrata, a human opportunistic pathogen is characterized by intrinsic, low susceptibility to fluconazole and a high capacity for acquiring high-level azole resistance. This is related to the elevated expression of genes belonging to the CgPdr1-governed regulon, comprising numerous genes, of which the multidrug ABC transporter-encoding CgCDR1, CgCDR2, CgSNQ2 are the best characterized. The function of certain PDR loci, such as CgRTA1 and CgRSB1 is poorly understood. These are homologs of ScRTA1 and ScRSB1 from Saccharomyces cerevisiae, members of the LTE family of plasma membrane proteins characteristic of fungi. While overproduced, they are involved in tolerance to 7-aminocholesterol or phytosphingosine, respectively. In this report we shed light on the differential regulation of CgRTA1 and CgRSB1 in C. glabrata. CgRTA1 expression positively correlated with intrinsic azole tolerance in clinical isolates. In contrast to CgRSB1, a high induction of CgRTA1 was observed upon fluconazole exposure, which was accompanied by a parallel up-regulation of its transcriptional activator CgPDR1. Hypoxia or presence of ketoconazole, both leading to ergosterol depletion, resulted in increased level of CgRTA1 transcript, whereas CgRSB1 was highly responsive to mitochondrial dysfunction. On the other hand, the expression of CgRTA1 was suppressed during growth in pseudohyphae formation promoting media. Our results are the first report linking the divergent regulation of LTE family members and azole sensitivity in C. glabrata.
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PMID:Differential expression of the Candida glabrata CgRTA1 and CgRSB1 genes in response to various stress conditions. 2333 99