Antitumor activity of an allosteric inhibitor of centromere-associated protein-E
Antitumor activity of an allosteric inhibitor of centromere-associated protein-E
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DOI：
10.1073/pnas.0915068107
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发表时间：
2010-03-30
影响因子：
11.1
通讯作者：
Jackson, Jeffrey R.
中科院分区：
文献类型：
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作者：
Wood, Kenneth W.;Lad, Latesh;Jackson, Jeffrey R.
着丝粒相关蛋白-E(CENP-E)是一种动粒相关的有丝分裂激动素，在与纺锤体微管相互作用后，被认为是负责有丝分裂检查点信号转导的关键受体。我们已经鉴定了CENP-E运动蛋白马达ATPase活性的变构抑制剂GSK923295，并将其结合位点定位到与KSP/EG5运动蛋白KSP/EG5的loop-5抑制剂结合的区域。与这些阻止ADP释放并破坏运动-微管相互作用的KSP抑制剂不同，GSK923295抑制无机磷的释放并稳定CENP-E运动域与微管的相互作用。抑制CENP-E在培养细胞和肿瘤移植瘤中的运动活性会导致中期染色体排列失败和诱导有丝分裂停止，这表明CENP-E与微管的紧密结合不足以满足有丝分裂检查点。与小鼠遗传学研究一致，提示CENP-E功能降低可起到抑瘤作用，抑制CENP-E诱导的肿瘤细胞凋亡和肿瘤消退。
Centromere-associatedprotein-E(CENP-E) is akinetochore-associated mitotic kinesin that is thought to function as the key receptor responsible for mitotic checkpoint signal transduction after interaction with spindle microtubules. We have identified GSK923295, an allosteric inhibitor of CENP-E kinesin motor ATPase activity, and mapped the inhibitor binding site to a region similar to that bound by loop-5 inhibitors of the kinesin KSP/Eg5. Unlike these KSP inhibitors, which block release of ADP and destabilize motor-microtubule interaction, GSK923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor-suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression.