Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells.
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.
Radhakrishnan
Senthil K
SK
Division of Biology, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
Lee
Candy S
CS
Young
Patrick
P
Beskow
Anne
A
Chan
Jefferson Y
JY
Deshaies
Raymond J
RJ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007976:Leupeptins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D051266:Nuclear Respiratory Factor 1; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C496381:YU101; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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