The transcription factor Ndt80 does not contribute to Mrr1-, Tac1-, and Upc2-mediated fluconazole resistance in Candida albicans.
The transcription factor Ndt80 does not contribute to Mrr1-, Tac1-, and Upc2-mediated fluconazole resistance in Candida albicans.
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DOI：
10.1371/journal.pone.0025623
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Morschhäuser J
中科院分区：
文献类型：
--
作者：
Sasse C;Schillig R;Dierolf F;Weyler M;Schneider S;Mogavero S;Rogers PD;Morschhäuser J
致病性酵母菌白色念珠菌可通过编码多药外排泵或麦角固醇生物合成酶的基因的过表达而对广泛使用的抑制麦角固醇生物合成的抗真菌剂氟康唑产生抗性。锌簇转录因子在耐药性的转录调控中起着核心作用。Mrr 1调节主要促进剂MDR 1的表达，Tac 1控制ABC转运蛋白CDR 1和CDR 2的表达，Upc 2调节麦角固醇生物合成（ERG）基因。这些转录因子的功能获得性突变导致其靶基因的组成性过表达，并导致许多临床念珠菌的氟康唑耐药。白色念珠菌分离株。转录因子Ndt 80参与药物诱导的CDR 1和ERG基因的上调，并与MDR 1和CDR 2启动子结合，这表明它是氟康唑耐药的所有主要转录机制的重要组成部分。然而，我们发现Ndt 80不是诱导化学物质诱导MDR 1和CDR 2表达所必需的。CDR 2在Ndt 80 Δ突变体中甚至部分去阻遏，表明Ndt 80是CDR 2表达的阻遏物。Mrr 1、Tac 1和Upc 2的高活性形式分别促进MDR 1、CDR 1/CDR 2和ERG 11的过表达，在Ndt 80存在和不存在的情况下具有相同的效率。与野生型细胞相比，Mrr 1和Tac 1介导的氟康唑耐药性在E80 Δ突变体中甚至略有增强。这些结果表明，Ndt 80是由于Mrr 1，Tac 1和Upc 2靶基因的组成性过表达以及这些转录因子中已获得激活突变的菌株的氟康唑耐药性增加而引起的。
The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis, by the overexpression of genes encoding multidrug efflux pumps or ergosterol biosynthesis enzymes. Zinc cluster transcription factors play a central role in the transcriptional regulation of drug resistance. Mrr1 regulates the expression of the major facilitator MDR1, Tac1 controls the expression of the ABC transporters CDR1 and CDR2, and Upc2 regulates ergosterol biosynthesis (ERG) genes. Gain-of-function mutations in these transcription factors result in constitutive overexpression of their target genes and are responsible for fluconazole resistance in many clinical C. albicans isolates. The transcription factor Ndt80 contributes to the drug-induced upregulation of CDR1 and ERG genes and also binds to the MDR1 and CDR2 promoters, suggesting that it is an important component of all major transcriptional mechanisms of fluconazole resistance. However, we found that Ndt80 is not required for the induction of MDR1 and CDR2 expression by inducing chemicals. CDR2 was even partially derepressed in ndt80Δ mutants, indicating that Ndt80 is a repressor of CDR2 expression. Hyperactive forms of Mrr1, Tac1, and Upc2 promoted overexpression of MDR1, CDR1/CDR2, and ERG11, respectively, with the same efficiency in the presence and absence of Ndt80. Mrr1- and Tac1-mediated fluconazole resistance was even slightly enhanced in ndt80Δ mutants compared to wild-type cells. These results demonstrate that Ndt80 is dispensable for the constitutive overexpression of Mrr1, Tac1, and Upc2 target genes and the increased fluconazole resistance of strains that have acquired activating mutations in these transcription factors.
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影响因子：
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作者：
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