Article abstract
Nature Chemical Biology 4, 548 - 556 (2008)
Published online: 10 August 2008 | doi:10.1038/nchembio.106
Cytosporone B is an agonist for nuclear orphan receptor Nur77
Yanyan Zhan1,3, Xiping Du1,3, Hangzi Chen1, Jingjing Liu1, Bixing Zhao1, Danhong Huang1, Guideng Li1, Qingyan Xu1, Mingqing Zhang1, Bart C Weimer2, Dong Chen2, Zhe Cheng1, Lianru Zhang1, Qinxi Li1, Shaowei Li1, Zhonghui Zheng1, Siyang Song1, Yaojian Huang1, Zhiyun Ye1, Wenjin Su1, Sheng-Cai Lin1, Yuemao Shen1 & Qiao Wu1
Abstract
Nuclear orphan receptor Nur77 has important roles in many biological processes. However, a physiological ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing positive autoregulation in a Csn-B–dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biological effects were not observed in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biological function.
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 422 South Siming Road, Xiamen, Fujian 361005, China.
- Center for Integrated BioSystems, Utah State University, 4700 Old Main Hill, Logan, Utah 84322, USA.
- These authors contributed equally to this work.
Correspondence to: Qiao Wu1 e-mail: qiaow@xmu.edu.cn
Correspondence to: Yuemao Shen1 e-mail: yshen@xmu.edu.cn
Correspondence to: Sheng-Cai Lin1 e-mail: linsc@xmu.edu.cn
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