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 journalArticle

173 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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  • Cite this

    Zhan, Y., Du, X., Chen, H., Liu, J., Zhao, B., Huang, D., Li, G., Xu, Q., Zhang, M., Weimer, B. C., Chen, D., Cheng, Z., Zhang, L., Li, Q., Li, S., Zheng, Z., Song, S., Huang, Y., Ye, Z., ... Wu, Q. (2008). Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nature Chemical Biology, 4(9), 548-556. https://doi.org/10.1038/nchembio.106