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.
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We are grateful to S. Safe (Institute of Biosciences and Technology, Texas A&M University Health Science Center) for the vectors of GAL4-Nur77 and GAL4-LBD. We also thank F. Chen (Cancer Research Center, Xiamen University) for help with mouse experiments. This work was supported by grants from the National Natural Science Fund of China (30630070 and 30425014 to Q.W., 30325044 to Y.S.), grants from the “973” Project of the Ministry of Science and Technology (2006CB503905 to S.-C.L., 2004CB518800 and 2007CB914402 to Q.W.) and grants from the Ministry of Education (706036 to Q.W., 306010 to Y.S. and 705030 to S.-C.L.). Q.W., Y.S. and S.-C.L. are recipients of the National Science Fund for Distinguished Young Scholars. S.-C.L. is a Cheung Kong Scholar.
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Zhan, Y., Du, X., Chen, H. et al. Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat Chem Biol 4, 548–556 (2008). https://doi.org/10.1038/nchembio.106
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