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 language | English (US) |
|---|---|
| Pages (from-to) | 548-556 |
| Number of pages | 9 |
| Journal | Nature Chemical Biology |
| Volume | 4 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
Cytosporone B is an agonist for nuclear orphan receptor Nur77. / Zhan, Yanyan; Du, Xiping; Chen, Hangzi; Liu, Jingjing; Zhao, Bixing; Huang, Danhong; Li, Guideng; Xu, Qingyan; Zhang, Mingqing; Weimer, Bart C; Chen, Dong; Cheng, Zhe; Zhang, Lianru; Li, Qinxi; Li, Shaowei; Zheng, Zhonghui; Song, Siyang; Huang, Yaojian; Ye, Zhiyun; Su, Wenjin; Lin, Sheng Cai; Shen, Yuemao; Wu, Qiao.
In: Nature Chemical Biology, Vol. 4, No. 9, 09.2008, p. 548-556.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cytosporone B is an agonist for nuclear orphan receptor Nur77
AU - Zhan, Yanyan
AU - Du, Xiping
AU - Chen, Hangzi
AU - Liu, Jingjing
AU - Zhao, Bixing
AU - Huang, Danhong
AU - Li, Guideng
AU - Xu, Qingyan
AU - Zhang, Mingqing
AU - Weimer, Bart C
AU - Chen, Dong
AU - Cheng, Zhe
AU - Zhang, Lianru
AU - Li, Qinxi
AU - Li, Shaowei
AU - Zheng, Zhonghui
AU - Song, Siyang
AU - Huang, Yaojian
AU - Ye, Zhiyun
AU - Su, Wenjin
AU - Lin, Sheng Cai
AU - Shen, Yuemao
AU - Wu, Qiao
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=49949089858&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=49949089858&partnerID=8YFLogxK
U2 - 10.1038/nchembio.106
DO - 10.1038/nchembio.106
M3 - Article
C2 - 18690216
AN - SCOPUS:49949089858
VL - 4
SP - 548
EP - 556
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 9
ER -