Cytosporone B is an agonist for nuclear orphan receptor Nur77

Nat Chem Biol. 2008 Sep;4(9):548-56. doi: 10.1038/nchembio.106.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents* / isolation & purification
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Apoptosis / drug effects
  • Ascomycota / chemistry
  • Blood Glucose / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / agonists*
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Gluconeogenesis / drug effects*
  • Gluconeogenesis / genetics
  • Humans
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Models, Molecular
  • Neoplasm Transplantation
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenylacetates* / isolation & purification
  • Phenylacetates* / pharmacology
  • Phenylacetates* / therapeutic use
  • Protein Binding
  • Protein Transport
  • Receptors, Steroid / agonists*
  • Receptors, Steroid / biosynthesis
  • Receptors, Steroid / genetics
  • Transcriptional Activation
  • Transfection
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Blood Glucose
  • DNA-Binding Proteins
  • Ligands
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenylacetates
  • Receptors, Steroid
  • cytosporone B

Associated data

  • PDB/2QW4