Photoswitchable CENP-E Inhibitor Enabling the Dynamic Control of Chromosome Movement and Mitotic Progression
Photoswitchable CENP-E Inhibitor Enabling the Dynamic Control of Chromosome Movement and Mitotic Progression
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DOI：
10.1021/jacs.9b12782
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发表时间：
2020-01-29
影响因子：
15
通讯作者：
Tamaoki, Nobuyuki
中科院分区：
文献类型：
--
作者：
Mafy, Noushaba Nusrat;Matsuo, Kazuya;Tamaoki, Nobuyuki
干扰有丝分裂是一种潜在的癌症治疗策略。然而，抗有丝分裂药物在细胞生长抑制中缺乏可控性，导致严重的副作用，并限制了它们的临床应用。在此，我们开发了一种基于偶氮苯的CENP-E光开关抑制剂，CENP-E是一种染色体运输所需的有丝分裂驱动蛋白。这种新的抑制剂能够实现CENP-E活性的可逆光开关，在体外和活细胞中，顺式和反式光异构化状态之间的IC 50变化类似于10倍。它还使CENP-E依赖性染色体聚集的可重复光开关成为可能，因此使有丝分裂进程能够与UV/可见光照射循环一起进行。使用这种技术，我们可以指定有丝分裂进程的确切过程中，CENP-E起着不可或缺的作用。我们的数据表明，一个高度可控的有丝分裂干扰，以及在动态细胞过程中发现精确的分子功能的光化学方法的力量。
Interfering with mitosis is a potential cancer therapy strategy. However, the lack of controllability of antimitotic drugs in cell growth suppression causes severe side effects and limits their clinical utility. Herein, we developed an azobenzene-based photoswitchable inhibitor of CENP-E, a mitotic kinesin required for chromosome transportation. The new inhibitor enabled reversible photoswitching of CENP-E activity with similar to 10-fold change in IC50 between cis and trans photoisomerization states both in vitro and in living cells. It also enabled repeatable photoswitching of CENP-E-dependent chromosome congression and hence mitotic progression with UV/vis light illumination cycles. Using this technique, we could specify the exact process of mitotic progression in which CENP-E plays an indispensable role. Our data demonstrate the power of a photochemical approach for highly controllable mitotic interference as well as for discovery of precise molecular functions in dynamic cellular processes.