Discovery of an NRF1-specific inducer from a large-scale chemical library using a direct NRF1-protein monitoring system

Tadayuki Tsujita, Liam Baird, Yuki Furusawa, Fumiki Katsuoka, Yoshika Hou, Satomi Gotoh, Shin Ichi Kawaguchi, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

NRF1 (NF-E2-p45-related factor 1) plays an important role in the regulation of genes encoding proteasome subunits, a cystine transporter, and lipid-metabolizing enzymes. Global and tissue-specific disruptions of the Nrf1 gene in mice result in embryonic lethality and spontaneous development of severe tissue defects, respectively, suggesting NRF1 plays a critical role in vivo. Mechanistically, the continuous degradation of the NRF1 protein by the proteasome is regarded as a major regulatory nexus of NRF1 activity. To develop NRF1-specific inducers that act to overcome the phenotypes related to the lack of NRF1 activity, we constructed a novel NRF1ΔC-Luc fusion protein reporter and developed cell lines that stably express the reporter in Hepa1c1c7 cells for use in high-throughput screening. In screening of a chemical library with this reporter system, we identified two hit compounds that significantly induced luciferase activity. Through an examination of a series of derivatives of one of the hit compounds, we identified T1-20, which induced a 70-fold increase in luciferase activity. T1-20 significantly increased the level of NRF1 protein in the mouse liver, indicating that the compound is also functional invivo. Thus, these results show the successful identification of the first small chemical compounds which specifically and significantly induce NRF1.

Original languageEnglish
Pages (from-to)563-577
Number of pages15
JournalGenes to Cells
Volume20
Issue number7
DOIs
Publication statusPublished - 2015 Jul 1

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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