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.

Molecular signatures of thyroid follicular neoplasia

“…Moreover, this finding is supported by two recent studies where NR4A1 was found to be down-regulated in FC (Fryknas et al 2006, Camacho et al 2009). NR4A1 and NR4A3 also known as Nur77 and Nor-1 respectively are homologous orphan nuclear receptors that regulate the transcription of a common set of target genes (Li et al 2006), and both have been described as homeostatic regulators of proliferation and apoptosis (Moll et al 2006, Zhan et al 2008. While NR4A1-and NR4A3-deficient mice respectively exhibit subtle phenotypes, it was recently shown that double knockout quickly leads to acute myeloid leukemia.…”

Total Synthesis of Cytosporone B

“…1 Some of them display antibacterial activity. [1][2][3] Particularly, a recent excellent report by Wu et al 4 has revealed that Cytosporone B acted as an agonist for Nur77. Nuclear receptors play important roles in numerous biological processes such as cell proliferation, differentiation, apoptosis, metabolism and development.…”

“…These results reveal that Cytosporone B may be useful in the development of new therapeutic drugs to treat cancer and hypoglycemia. 4 The novel structures of Cytosporone B combining with remarkable biological activity and lack of availability from natural sources have attracted interest from chemists for its total synthesis. In the following we report on the total synthesis of this compound.…”

“…Remarkably, Cytosporone B is a naturally occurring agonist for Nur77. 4 It has a strong affinity for Nur77 and stimulates the transactivational activity of Nur77. Moreover, it increases Nur77-mediated induction of apoptosis, increases growth inhibition of xenograft tumors in nude mice, and enhances gluconeogenesis in mouse liver.…”

Ligand-gated Ion Channels

“…May be activated by DY131 Nur77 NR4A1 Nerve growth factor IB, NGFI-B, NAK1, ST59, TR3, HMR ENSG00000123358 An exogenous agonist, cytosporone B, has been described (Zhan et al, 2008), although structural analysis and molecular modelling has not identified a ligand binding site (Baker et al, 2003;Flaig et al, 2005; Liver X and farnesoid X Overview: Liver X and farnesoid X receptors (LXR and FXR, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see are members of a steroid analogue-activated nuclear receptor subfamily (ENSF00000000720), which form heterodimers with members of the retinoid X receptor family. Endogenous ligands for LXRs include hydroxycholesterols (OHC), while FXRs appear to be activated by bile acids.…”