Chemical genetic modifier screens: Small molecule trichostatin suppressors as probes of intracellular histone and tubulin acetylation
Chemical genetic modifier screens: Small molecule trichostatin suppressors as probes of intracellular histone and tubulin acetylation
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DOI：
10.1016/s1074-5521(03)00093-0
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发表时间：
2003-05-01
影响因子：
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通讯作者：
Schreiber, SL
中科院分区：
文献类型：
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作者：
Koeller, KM;Haggarty, SJ;Schreiber, SL
组蛋白去乙酰化酶（HDAC）抑制剂正在被开发为癌症治疗中的新临床药物，部分原因是它们中断了转化细胞系中的细胞周期进程。为了检查由HDAC抑制剂阿司他丁A（TSA）诱导的细胞周期停滞，使用基于细胞周期的筛选来鉴定该过程的小分子抑制剂。TSA抑制子（ITSAs）可对抗TSA诱导的细胞周期停滞、组蛋白乙酰化和转录激活。基于异羟肟酸的HDAC抑制剂如TSA和辛二酰苯胺异羟肟酸（SAHA）促进细胞质α-微管蛋白以及组蛋白的乙酰化，这种修饰也被ITSA抑制。虽然微管蛋白乙酰化似乎与细胞周期进程和转录无关，但它可能在其他细胞过程中发挥作用。小分子抑制剂，如ITSA，可从化学遗传抑制筛选，可能被证明是许多生物过程的有价值的探针。
Histone deacetylase (HDAC) inhibitors are being developed as new clinical agents in cancer therapy, in part because they interrupt cell cycle progression in transformed cell lines. To examine cell cycle arrest induced by HDAC inhibitor trichostatin A (TSA), a cytoblot cell-based screen was used to identify small molecule suppressors of this process. TSA suppressors (ITSAs) counteract TSA-induced cell cycle arrest, histone acetylation, and transcriptional activation. Hydroxamic acid-based HDAC inhibitors like TSA and suberoylanilide hydroxamic acid (SAHA) promote acetylation of cytoplasmic a-tubulin as well as histones, a modification also suppressed by ITSAs. Although tubulin acetylation appears irrelevant to cell cycle progression and transcription, it may play a role in other cellular processes. Small molecule suppressors such as the ITSAs, available from chemical genetic suppressor screens, may prove to be valuable probes of many biological processes.