Transcription Factor Nrf1 Mediates the Proteasome Recovery Pathway after Proteasome Inhibition in Mammalian Cells

• Published in: Molecular cell Vol. 38; no. 1; pp. 17 - 28
• Main Authors: Radhakrishnan, Senthil K., Lee, Candy S., Young, Patrick, Beskow, Anne, Chan, Jefferson Y., Deshaies, Raymond J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.04.2010
• Subjects: Animals; Antineoplastic Agents - metabolism; Antioxidants; Antioxidants - metabolism; Apoptosis - physiology; Base Sequence; Cell Line, Tumor; CELLCYCLE; Cells, Cultured; Cysteine Proteinase Inhibitors - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Regulation; Humans; Leupeptins - metabolism; Mice; Mice, Knockout; Molecular Biology; Molecular Sequence Data; molekylärbiologi; Nuclear Respiratory Factor 1 - genetics; Nuclear Respiratory Factor 1 - metabolism; Oligopeptides - genetics; Oligopeptides - metabolism; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; PROTEINS; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; PROTEINS; CELLCYCLE
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2010.02.029

In Saccharomyces cerevisiae, chemical or genetic inhibition of proteasome activity induces new proteasome synthesis promoted by the transcription factor RPN4. This ensures that proteasome activity is matched to demand. This transcriptional feedback loop is conserved in mammals, but its molecular basis is not understood. Here, we report that nuclear factor erythroid-derived 2-related factor 1 (Nrf1), a transcription factor of the cap “n” collar basic leucine zipper family, but not the related Nrf2, is necessary for induced proteasome gene transcription in mouse embryonic fibroblasts (MEFs). Promoter-reporter assays revealed the importance of antioxidant response elements in Nrf1-mediated upregulation of proteasome subunit genes. Nrf1−/− MEFs were impaired in the recovery of proteasome activity after transient treatment with the covalent proteasome inhibitor YU101, and knockdown of Nrf1 in human cancer cells enhanced cell killing by YU101. Taken together, our results suggest that Nrf1-mediated proteasome homeostasis could be an attractive target for therapeutic intervention in cancer. ► Nrf1 mediates proteasome inhibitor-induced proteasome gene transcription ► Nrf1 depletion sensitizes cancer cells to covalent proteasome inhibitor treatment