http://news.sciencenet.cn//htmlnews/2010/4/230670.shtm 《科学》:我国白血病研究又获重大突破 发现抗急性早幼粒细胞白血病药物三氧化二砷的作用靶点 上海交通大学医学院附属瑞金医院上海血液学研究所/医学基因组学国家重点实验室4月9日在国际权威杂志《科学》( Science )上发表了三氧化二砷治疗急性早幼粒细胞性白血病(APL)分子机制的最新研究成果,该研究揭示了癌蛋白PML-RAR 是砷剂治疗APL的直接药物靶点。他们发现三氧化二砷直接与癌蛋白PML端的锌指结构中的半胱氨酸结合,诱导蛋白质发生构象变化和多聚化,继而发生SUMO化、泛素化修饰而被蛋白酶体降解。癌蛋白的降解最终导致白血病细胞走向分化和凋亡。使APL成为人类急性白血病分子靶向治疗取得临床治愈的成功范例。这一成果丰富了APL靶向治疗的理论,对于推动其它类型白血病和实体瘤的分子靶向治疗研究也具有十分重要的指导意义。 http://www.sciencemag.org/cgi/content/abstract/328/5975/240 Science 9 April 2010: Vol. 328. no. 5975, pp. 240 - 243 DOI: 10.1126/science.1183424 Prev | Table of Contents | Next Reports Arsenic Trioxide Controls the Fate of the PML-RAR Oncoprotein by Directly Binding PML Xiao-Wei Zhang, 1 ,* Xiao-Jing Yan, 1 ,* Zi-Ren Zhou, 2 Fei-Fei Yang, 3 Zi-Yu Wu, 3 Hong-Bin Sun, 4 Wen-Xue Liang, 1 Ai-Xin Song, 2 Valrie Lallemand-Breitenbach, 5 Marion Jeanne, 5 Qun-Ye Zhang, 1 Huai-Yu Yang, 6 Qiu-Hua Huang, 1 Guang-Biao Zhou, 7 Jian-Hua Tong, 1 Yan Zhang, 1 Ji-Hui Wu, 4 Hong-Yu Hu, 2 Hugues de Th, 5 ,8 Sai-Juan Chen, 1 ,8 , Zhu Chen 1 ,8 , 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 (As 2 O 3 ) 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-RAR degradation is triggered by their SUMOylation, but the mechanism by which As 2 O 3 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 As 2 O 3 provides new insights into the drugs mechanism of action and its specificity for APL. 1 State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China. 2 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai 200031, China. 3 National Synchrotron Radiation Laboratory, University of Science and Technology of China and Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, CAS, Beijing 10004, China. 4 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China. 5 Universit de Paris 7/INSERM/CNRS UMR 944/7151, Equipe Labellise No. 11 Ligue Nationale Contre le Cancer, Hpital St. Louis, Avenue C. Vellefaux, 75475 Paris CEDEX 10, France. 6 Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, CAS, Shanghai 201203, China. 7 Laboratory of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, and Key Laboratory of Stem Cell Development, Institute of Zoology, CAS, Beijing, China. 8 The Ple Sino-Franais de gnomique et de Sciences du vivant de lHpital Rui-Jin, 197 Rui-Jin Road II, Shanghai, China. * These authors contributed equally to this work. To whom correspondence should be addressed. E-mail: zchen@stn.sh.cn