Cytosporone B is an agonist for nuclear orphan receptor Nur77.
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.
Zhan
Yanyan
Y
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.
Du
Xiping
X
Chen
Hangzi
H
Liu
Jingjing
J
Zhao
Bixing
B
Huang
Danhong
D
Li
Guideng
G
Xu
Qingyan
Q
Zhang
Mingqing
M
Weimer
Bart C
BC
Chen
Dong
D
Cheng
Zhe
Z
Zhang
Lianru
L
Li
Qinxi
Q
Li
Shaowei
S
Zheng
Zhonghui
Z
Song
Siyang
S
Huang
Yaojian
Y
Ye
Zhiyun
Z
Su
Wenjin
W
Lin
Sheng-Cai
SC
Shen
Yuemao
Y
Wu
Qiao
Q
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
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