Prostaglandin A₂ Acts as a Transactivator for NOR1 (NR4A3) within the Nuclear Receptor Superfamily

Abstract

Within the nuclear receptor superfamily, Nur77, Nurr1, and NOR1 constitute the nuclear receptor subfamily 4 group A. Modulation of NOR1 function would be therapeutic potential for diseases related to dysfunction of NOR1, including extraskeletal myxoid chondrosarcoma and autoimmune diseases. By screening arachidonate metabolites for their capacity of transcriptional activation, we have identified prostaglandin (PG) A₂ as a transactivator for NOR1. PGA₂ acted as a potent activator of NOR1-dependent transcription through the GAL4-based reporter system. The putative ligand-binding domain (LBD) of the receptor directly bound PGA₂, and LBD-deleted receptor showed little transcriptional activation by PGA₂. Primary cultured spleen cells derived from transgenic mice overexpressing NOR1, showed higher sensitivity to PGA₂ compared to those from wild-type mice. These observations suggest that PGA₂ can serve as a transactivator of NOR1, and thus suggest a possibility of pharmacological modulation of the NOR1 pathways by PGA₂-related compounds.