Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

查看全文 作　　者：Tao [1,2]Yu;Yonghui [1,2]Tao;Meiqiang [1]Yang;Peng [1,2]Chen;Xiaobo [1,2]Gao;Yanbo [2,3]Zhang;Tao [4]Zhang;Zi [5]Chen;Jian [6]Hou;Yan [7]Zhang;Kangcheng [1]Ruan;Hongyan [3]Wang;Ronggui [1,8]Hu

机构地区：[1]State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China;[2]Graduate School, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, Chin;[3]State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China;[4]Department of Laboratory Medicine, Hua-Shan Hospital, Fudan University, 12 Road Wulumuqi middle Road, Shanghai 200040, China;[5]Department of Hematology, Hua-Shan Hospital, Fudan University, 12 Road Wulumuqi middle Road, Shanghai 200040, China;[6]Department of Hematology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China;[7]Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China;[8]Cancer Research Center, SIBS-Xuhui Central Hospital, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, Chin

出　　处：《Cell Research》索引2014年第24卷第10期,共17页

基　　金：We are grateful to Dr W Bian and her team in Cell Biology Core facility of SIBCB for their excellent support in flow cytometry analysis and cell sorting, and Drs L Lin, Y Xia and H Xiao of National Center for Microarrays for their help in microarray analysis. We are particularly grateful to Dr Hsueh-Chi Yen at Institute of Mol Biol, Academia Sinica, and Dr Ivan Dikic of Goethe University for advice, and Drs Dangsheng Li, Lijian Hui and Jiarui Wu of SIBCB, and Dr Shirley Diamond of California Institute of Tech- nology for helpful discussion. We also thank Dr Ya-lan Wu and all other members of the Hu lab for support. This work was supported by the National Natural Science Foundation of China (31270828, 31070678, 81170491, 81072070 and 81470360), the 100 Talents award from CAS to RH and the Ministry of Science and Technology, China (2010CB912100, 2012CB910800 and 2013CB910900 to RH, and 2011CB915501 to KR). RH was also supported by a Sanofi-aventis SIBS Young Investigator award and funding from the Cancer Center of Xuhui Central Hospital (CCR2012003), Shanghai Institute of Neurosciences (SKLN-201206) and the Instrument Developing Project of the Chinese Academy of Sciences (YZ201339). 摘　　要：在蛋白质周转(蛋白质 degradome ) 的全球变化组成对内在或外来的刺激的细胞的回答的中央部分。然而,介绍蛋白质 degradome 仍然保持技术上挑战性。最近, proteasome 的抑制,例如由使用 bortezomib (BTZ ) ,为对待多重骨髓瘤和其它人恶意,但是药行动和肿瘤药抵抗还有待于被完成的为 BTZ 的机制的系统的理解作为主要化学疗法的策略出现了。这里,我们开发了并且适用 dual-fluorescence-based 蛋白质周转试金(ProTA ) 到份量上在导致 BTZ 的 proteasomal 抑制之上在人的蛋白质 degradome 介绍全球变化。ProTA 和随后的网络分析描出在 BTZ 化疗的 BTZ 行动和肿瘤药抵抗的潜在的分子的基础。最后,把 BTZ 的使用与指向识别 ProTA 的关键基因的药相结合或在 BTZ 行动的小径在多重骨髓瘤房间减少了 BTZ 抵抗。显著地, BTZ 稳定 proteasome 子单元 PSMC1 和 proteasome 集会因素 PSMD10,建议为调整 proteasome 动态平衡的以前下面欣赏的机制。因此, ProTA 是为介绍人的蛋白质 degradome 阐明的一个新奇工具药行动和抵抗的潜在的机制,它可能便于指向 proteostasis 对待人的混乱的治疗学的开发。 关键词：人类蛋白质骨髓瘤细胞蛋白酶体耐药机制解组多发性骨髓瘤化学治疗稳态

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Profiling human protein degradome delineates cellular responses to proteasomal inhibition and reveals a feedback mechanism in regulating proteasome homeostasis

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