Cytosporone B is an agonist for nuclear orphan receptor Nur77

• DOI: 10.1038/nchembio.106
• Publication Date: 2008-08-10T17:05:51Z
• Authors: 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
• Keywords: Orphan receptor

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.