Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML
Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML
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DOI：
10.1126/science.1183424
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发表时间：
2010-04-09
期刊：
影响因子：
56.9
通讯作者：
Chen, Zhu
中科院分区：
文献类型：
--
作者：
Zhang, Xiao-Wei;Yan, Xiao-Jing;Chen, Zhu
砷是一种古老的中药，因其对急性早幼粒细胞白血病（APL）患者具有显著的抗癌活性而引起世界各国的关注。三氧化二砷（As 2 O3）通过促进驱动APL细胞生长的致癌蛋白PML-RAR α（一种融合蛋白，含有PML锌指蛋白和视黄酸受体α的序列）的降解来发挥其治疗作用。PML和PML-RAR α降解是由它们的SUMO化引发的，但As 2 O3诱导这种翻译后修饰的机制尚不清楚。在这里，我们表明砷直接结合到半胱氨酸残基的锌指位于RBCC结构域的PML-RAR α和PML。砷结合诱导PML寡聚化，这增加了其与小泛素样蛋白修饰剂（SUMO）缀合酶UBC 9的相互作用，导致SUMO化和降解增强。PML作为As 2 O3的直接靶点的鉴定为药物的作用机制及其对APL的特异性提供了新的见解。
Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RAR alpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RAR alpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RAR alpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.