BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites

Bruce Blumberg, Heonjoong Kang, Jack Bolado, Hongwu Chen, A. Grey Craig, Tanya A. Moreno, Kazuhiko Umesono, Thomas Perlmann, Eddy M. De Robertis, Ronald M. Evans

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Nuclear receptors are ligand-modulated transcription factors that respond to steroids, retinoids, and thyroid hormones to control development and body physiology. Orphan nuclear receptors, which lack identified ligands, provide a unique, and largely untapped, resource to discover new principles of physiologic homeostasis. We describe the isolation and characterization of the vertebrate orphan receptor, BXR, which heterodimerizes with RXR and binds high-affinity DNA sites composed of a variant thyroid hormone response element. A bioactivity-guided screen of embryonic extracts revealed that BXR is activatable by low-molecular-weight molecules with spectral patterns distinct from known nuclear receptor ligands. Mass spectrometry and 1H NMR analysis identified alkyl esters of amino and hydroxy benzoic acids as potent, stereoselective activators. In vitro cofactor association studies, along with competable binding of radiolabeled compounds, establish these molecules as bona fide ligands. Benzoates comprise a new molecular class of nuclear receptor ligand and their activity suggests that BXR may control a previously unsuspected vertebrate signaling pathway.

Original languageEnglish (US)
Pages (from-to)1269-1277
Number of pages9
JournalGenes and Development
Volume12
Issue number9
StatePublished - May 1 1998
Externally publishedYes

Keywords

  • Benzoates
  • BXR
  • Vertebrate signaling pathway
  • Xenopus Orphan nuclear receptor

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Blumberg, B., Kang, H., Bolado, J., Chen, H., Craig, A. G., Moreno, T. A., Umesono, K., Perlmann, T., De Robertis, E. M., & Evans, R. M. (1998). BXR, an embryonic orphan nuclear receptor activated by a novel class of endogenous benzoate metabolites. Genes and Development, 12(9), 1269-1277.