Natural Product Triptolide Mediates Cancer Cell Death by Triggering CDK7-Dependent Degradation of RNA Polymerase II

doi:10.1158/0008-5472.CAN-12-1006

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	Natural Product Triptolide Mediates Cancer Cell Death by Triggering CDK7-Dependent Degradation of RNA Polymerase II
	Manzo, Stefano Giustino 1; Zhou, Zhao-Li 2; Wang, Ying-Qing2 ; Marinello, Jessica 1; He, Jin-Xue 2; Li, Yuan-Chao 3; Ding, Jian2 ; Capranico, Giovanni 1; Miao, Ze-Hong 2
刊名	CANCER RESEARCH
	2012-10-15
卷号	72 期号:20 页码:5363-5373
ISSN号	0008-5472
DOI	10.1158/0008-5472.CAN-12-1006
文献子类	Article
英文摘要	Triptolide is a bioactive ingredient in traditional Chinese medicine that exhibits diverse biologic properties, including anticancer properties. Among its many putative targets, this compound has been reported to bind to XPB, the largest subunit of general transcription factor TFIIH, and to cause degradation of the largest subunit Rpb1 of RNA polymerase II (RNAPII). In this study, we clarify multiple important questions concerning the significance and basis for triptolide action at this core target. Triptolide decreased Rpb1 levels in cancer cells in a manner that was correlated tightly with its cytotoxic activity. Compound exposure blocked RNAPII at promoters and decreased chromatin-bound RNAPII, both upstream and within all genes that were examined, also leading to Ser-5 hyperphosphorylation and increased ubiqutination within the Rbp1 carboxy-terminal domain. Notably, cotreatment with inhibitors of the proteasome or the cyclin-dependent kinase CDK7 inhibitors abolished the ability of triptolide to ablate Rpb1. Together, our results show that triptolide triggers a CDK7-mediated degradation of RNAPII that may offer an explanation to many of its therapeutic properties, including its robust and promising anticancer properties. Cancer Res; 72(20); 5363-73. (C) 2012 AACR.
资助项目	National Natural Science Foundation of China (NSFC)[81025020] ; National Natural Science Foundation of China (NSFC)[81021062] ; National Basic Research Program of China[2012CB932502] ; National Science & Technology Major Project of China[2012ZX09301-001-002] ; Shanghai Postdoctoral Scientific Program[11R21421300] ; China Postdoctoral Science Foundation[2011M500829] ; Chinese Academy of Sciences[00000000] ; "Associazione Italiana per la Ricerca sul Cancro" (AIRC), Milan, Italy[10184] ; University of Bologna[00000000]
WOS关键词	DNA TOPOISOMERASE-I ; LARGE SUBUNIT ; TRANSCRIPTIONAL ARREST ; TFIIH ; PHOSPHORYLATION ; UBIQUITINATION ; REPAIR ; XPB ; INHIBITION ; MECHANISMS
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000309972700025
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277909]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Miao, Ze-Hong
作者单位	1.Univ Bologna, Dept Pharmacol & BioTechnol, I-40126 Bologna, Italy; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Manzo, Stefano Giustino,Zhou, Zhao-Li,Wang, Ying-Qing,et al. Natural Product Triptolide Mediates Cancer Cell Death by Triggering CDK7-Dependent Degradation of RNA Polymerase II[J]. CANCER RESEARCH,2012,72(20):5363-5373.
APA	Manzo, Stefano Giustino.,Zhou, Zhao-Li.,Wang, Ying-Qing.,Marinello, Jessica.,He, Jin-Xue.,...&Miao, Ze-Hong.(2012).Natural Product Triptolide Mediates Cancer Cell Death by Triggering CDK7-Dependent Degradation of RNA Polymerase II.CANCER RESEARCH,72(20),5363-5373.
MLA	Manzo, Stefano Giustino,et al."Natural Product Triptolide Mediates Cancer Cell Death by Triggering CDK7-Dependent Degradation of RNA Polymerase II".CANCER RESEARCH 72.20(2012):5363-5373.