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Arsenic Trioxide Controls the Fate of the PML-RAR Oncoprotein by Directly Binding PML

热3 shizhao 添加于 2010-4-12 20:04 | 2761 次阅读 | 2 个评论

作者
Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de The H, Chen SJ, Chen Z
摘要
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 (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARdegradation 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 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.
详细资料
- 文献种类: Journal Article
- 期刊名称: Science
- 期刊缩写: Science
- 期卷页: 2010年第328卷第5975期 240-243页
- ISBN: 0036-8075
学科领域生物医药 » 基础医学
标签

砒霜白血病砷
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