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 SuSheng Cai Lin, Yuemao Shen, Qiao Wu

Research output: Contribution to journalArticlepeer-review

195 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)548-556
Number of pages9
JournalNature Chemical Biology
Volume4
Issue number9
DOIs
StatePublished - Sep 2008
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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