Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae
Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae
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DOI：
10.1074/jbc.m007338200
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发表时间：
2000-12-01
影响因子：
4.8
通讯作者：
Moye-Rowley, WS
中科院分区：
文献类型：
--
作者：
Hallstrom, TC;Moye-Rowley, WS
由于Cys（6）-Zn（II）转录因子Pdr 1 p和Pdr 3 p内的置换突变，酿酒酵母中最常发生多重或多效性耐药。这些显性转录调节蛋白引起耐药性升高和ATP结合盒转运蛋白编码基因PDR 5的过度表达。我们已经进行了遗传筛选，以确定PDR 5表达的负调控因子，并发现线粒体基因组（rho（o）细胞）的丢失导致Pdr 3 p上调，但不Pdr 1 p功能。此外，线粒体内膜蛋白Oxa 1 p的丢失产生导致Pdr 3 p活性增加的信号。这两种线粒体缺陷都导致PDR 3结构基因的表达增加。重要的是，用于增强rho（o）细胞中Pdr 3 p功能的信号通路与口腔细胞中的不同。先前描述的核-线粒体信号传导基因如RTG 1的缺失降低了rho（o）细胞中观察到的PDR 5表达水平和耐药性，但对oxa 1诱导的表型没有影响。这些数据揭示了一个新的调节途径连接多药耐药基因的表达与线粒体功能。
Multiple or pleiotropic drug resistance most often occurs in Saccharomyces cerevisiae due to substitution mutations within the Cys(6)-Zn(II) transcription factors Pdr1p and Pdr3p. These dominant transcriptional regulatory proteins cause elevated drug resistance and overexpression of the ATP-binding cassette transporter-encoding gene, PDR5. We have carried out a genetic screen to identify negative regulators of PDR5 expression and found that loss of the mitochondrial genome (rho (o) cells) causes up-regulation of Pdr3p but not Pdr1p function. Additionally, loss of the mitochondrial inner membrane protein Oxa1p generates a signal that results in increased Pdr3p activity. Both of these mitochondrial defects lead to increased expression of the PDR3 structural gene. Importantly, the signaling pathway used to enhance Pdr3p function in rho (o) cells is not the same as in oral cells. Loss of previously described nuclear-mitochondrial signaling genes like RTG1 reduce the level of PDR5 expression and drug resistance seen in rho (o) cells but has no effect on oxa1-induced phenotypes. These data uncover a new regulatory pathway connecting expression of multidrug resistance genes with mitochondrial function.