Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341
Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341
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DOI：
10.1073/pnas.032516399
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发表时间：
2002-02-05
影响因子：
11.1
通讯作者：
Blackman, RK
中科院分区：
文献类型：
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作者：
Fleming, JA;Lightcap, ES;Blackman, RK
尽管大多数药物的生化目标是已知的，但它们的作用的生物学后果通常不太清楚。在这项研究中，我们在酿酒酵母中使用了两种全基因组技术来确定蛋白酶体抑制剂PS-341对细胞的影响。通过结合群体基因组学、筛选一组全面的条形码突变菌株和转录谱，我们已经确定了受蛋白酶体抑制影响最大的基因和途径。它们中的许多参与调节蛋白质降解或有丝分裂活动的子集。此外，我们发现Rpn4p是对细胞补偿蛋白酶体抑制能力最负责的转录因子。这些互补技术结合在一起，为阐明药物治疗的细胞分支提供了一种通用而强大的手段。
Although the biochemical targets of most drugs are known, the biological consequences of their actions are typically less well understood. in this study, we have used two whole-genome technologies in Saccharomyces cerevisiae to determine the cellular impact of the proteasome inhibitor PS-341. By combining population genomics, the screening of a comprehensive panel of bar-coded mutant strains, and transcript profiling, we have identified the genes and pathways most affected by proteasome inhibition. Many of these function in regulated protein degradation or a subset of mitotic activities. In addition, we identified Rpn4p as the transcription factor most responsible for the cell's ability to compensate for proteasome inhibition. Used together, these complementary technologies provide a general and powerful means to elucidate the cellular ramifications of drug treatment.