Discovery of an NRF1‐specific inducer from a large‐scale chemical library using a direct NRF1‐protein monitoring system. (4th May 2015)

• Record Type: Journal Article
• Authors: Tsujita, Tadayuki; Baird, Liam; Furusawa, Yuki; Katsuoka, Fumiki; Hou, Yoshika; Gotoh, Satomi; Kawaguchi, Shin‐ichi; Yamamoto, Masayuki
• Is Part Of: Genes to cells. Volume 20:Number 7(2015:Jul.)
• Page Start: 563
• Page End: 577
• Publication Date: 2015-05-04
• Subjects: Cytogenetics -- Periodicals; Cells -- Mechanical properties -- Periodicals; Molecular genetics -- Periodicals; Genes -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Biomechanics -- Periodicals; 571.6
• DOI: 10.1111/gtc.12248
• Languages: English
• ISSNs: 1356-9597

Abstract

<abstract abstract-type="main" id="gtc12248-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>Nrf1</italic> gene in mice result in embryonic lethality and spontaneous development of severe tissue defects, respectively, suggesting NRF1 plays a critical role <italic>in vivo</italic>. 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 <italic>in vivo</italic>. Thus, these results show the successful identification of the first small chemical compounds which specifically and significantly induce NRF1.</p> </abstract>