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

doi:10.1126/science.1183424

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Arsenic Trioxide Controls the Fate of the PML-RAR alpha Oncoprotein by Directly Binding PML
	Zhang, Xiao-Wei 7; Yan, Xiao-Jing 7; Zhou, Zi-Ren 6; Yang, Fei-Fei 4,5; Wu, Zi-Yu 4,5; Sun, Hong-Bin 2,3; Liang, Wen-Xue 7; Song, Ai-Xin 6; Lallemand-Breitenbach, Valerie 11; Jeanne, Marion 11
刊名	SCIENCE
	2010-04-09
卷号	328 期号:5975 页码:240-243
ISSN号	0036-8075
DOI	10.1126/science.1183424
文献子类	Article
英文摘要	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 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.
资助项目	863 Program[2006AA02A405] ; 973 Project[2010CB529201] ; 973 Project[2006CB910305] ; National Natural Science Foundation of China[30801372] ; National Natural Science Foundation of China[30623010] ; National Natural Science Foundation of China[30772744] ; National Natural Science Foundation of China[30830119] ; National Natural Science Foundation of China[10734070] ; Shanghai Municipal Commission for Science and Technology[07DZ05908] ; Shanghai Municipal Commission for Science and Technology[08DZ2200100] ; Samuel Waxman Cancer Research Foundation[00000000]
WOS关键词	ACUTE PROMYELOCYTIC LEUKEMIA ; TRANS-RETINOIC ACID ; INITIATING CELLS ; DEGRADATION ; RECEPTOR ; THERAPY ; PROTEINS ; EFFICACY ; DOMAIN ; AS2O3
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	AMER ASSOC ADVANCEMENT SCIENCE
WOS记录号	WOS:000276459600045
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278920]
专题	药物发现与设计中心
通讯作者	Chen, Sai-Juan
作者单位	1.CAS, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China; 3.Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China; 4.CAS, Inst High Energy Phys, Beijing Synchrotron Radiat Facil, Beijing 10004, Peoples R China; 5.Univ Sci & Technol China, Natl Synchrotron Radiat Lab, Beijing 10004, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China; 7.Shanghai Jiao Tong Univ, Rui Jin Hosp, Shanghai Inst Hematol, State Key Lab Med Genom,Sch Med, Shanghai 200025, Peoples R China; 8.Hop Rui Jin, Shanghai, Peoples R China 9.CAS, Inst Zool, Key Lab Stem Cell Dev, Beijing, Peoples R China; 10.CAS, Lab Mol Carcinogenesis & Targeted Therapy Canc, State Key Lab Biomembrane & Membrane Biotechnol, Beijing, Peoples R China;
推荐引用方式 GB/T 7714	Zhang, Xiao-Wei,Yan, Xiao-Jing,Zhou, Zi-Ren,et al. Arsenic Trioxide Controls the Fate of the PML-RAR alpha Oncoprotein by Directly Binding PML[J]. SCIENCE,2010,328(5975):240-243.
APA	Zhang, Xiao-Wei.,Yan, Xiao-Jing.,Zhou, Zi-Ren.,Yang, Fei-Fei.,Wu, Zi-Yu.,...&Chen, Zhu.(2010).Arsenic Trioxide Controls the Fate of the PML-RAR alpha Oncoprotein by Directly Binding PML.SCIENCE,328(5975),240-243.
MLA	Zhang, Xiao-Wei,et al."Arsenic Trioxide Controls the Fate of the PML-RAR alpha Oncoprotein by Directly Binding PML".SCIENCE 328.5975(2010):240-243.