title: Cytosporone B is an agonist for nuclear orphan receptor Nur77.
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.
authors.affiliation: 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.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhan
authors.forename: Xiping
authors.initials: X
authors.lastname: Du
authors.forename: Hangzi
authors.initials: H
authors.lastname: Chen
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.forename: Bixing
authors.initials: B
authors.lastname: Zhao
authors.forename: Danhong
authors.initials: D
authors.lastname: Huang
authors.forename: Guideng
authors.initials: G
authors.lastname: Li
authors.forename: Qingyan
authors.initials: Q
authors.lastname: Xu
authors.forename: Mingqing
authors.initials: M
authors.lastname: Zhang
authors.forename: Bart C
authors.initials: BC
authors.lastname: Weimer
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Zhe
authors.initials: Z
authors.lastname: Cheng
authors.forename: Lianru
authors.initials: L
authors.lastname: Zhang
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Li
authors.forename: Shaowei
authors.initials: S
authors.lastname: Li
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Zheng
authors.forename: Siyang
authors.initials: S
authors.lastname: Song
authors.forename: Yaojian
authors.initials: Y
authors.lastname: Huang
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Ye
authors.forename: Wenjin
authors.initials: W
authors.lastname: Su
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001203:Ascomycota / Q000737:chemistry; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010648:Phenylacetates / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D021381:Protein Transport; D011987:Receptors, Steroid / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; D004268:DNA-Binding Proteins; D008024:Ligands; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010648:Phenylacetates; D011987:Receptors, Steroid; C531461:cytosporone B