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Abstract
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.
2010 Elsevier Inc. All rights reserved.