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Nature Chemical Biology 4, 548–556 (1 September 2008) | doi:10.1038/nchembio.106

Cytosporone B is an agonist for nuclear orphan receptor Nur77

Yanyan Zhan , Xiping Du , Hangzi Chen , Jingjing Liu , Bixing Zhao , Danhong Huang , Guideng Li , Qingyan Xu , Mingqing Zhang , Bart C Weimer , Dong Chen , Zhe Cheng , Lianru Zhang , Qinxi Li , Shaowei Li , Zhonghui Zheng , Siyang Song , Yaojian Huang , Zhiyun Ye , Wenjin Su , Sheng-Cai Lin , Yuemao Shen & Qiao Wu

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|[minus]|/|[minus]|) 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.