Cytosporone B is an agonist for nuclear orphan receptor Nur77

  • Nat Chem Biol. 2008 Sep;4(9):548-56. doi: 10.1038/nchembio.106.
Yanyan Zhan  1 ,  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
Affiliations
  • 1. 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.
PMID: 18690216 DOI: 10.1038/nchembio.106
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.

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