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

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  • Kagaya Shinji
    Genox Research Inc. Research Unit for Allergy Transcriptome, Research Center for Allergy & Immunology, RIKEN Yokohama Institute
  • Ohkura Naganari
    Tumor Endocrinology Project, National Cancer Center Research Institute, Japan
  • Tsukada Toshihiko
    Tumor Endocrinology Project, National Cancer Center Research Institute, Japan
  • Miyagawa Masami
    Genox Research Inc.
  • Sugita Yuji
    Genox Research Inc.
  • Tsujimoto Gozoh
    Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University
  • Matsumoto Kenji
    Department of Allergy and Immunology, National Research Institute for Child Health and Development, Japan
  • Saito Hirohisa
    Research Unit for Allergy Transcriptome, Research Center for Allergy & Immunology, RIKEN Yokohama Institute Department of Allergy and Immunology, National Research Institute for Child Health and Development, Japan
  • Hashida Ryoichi
    Genox Research Inc.

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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.

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