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Published April 9, 2010 | Accepted Version + Supplemental Material
Journal Article Open

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.

Additional Information

© 2010 Elsevier. Received 18 December 2009; revised 10 February 2010; accepted 26 February 2010. Published: April 8, 2010. Available online 8 April 2010. We thank Millenium Pharmaceuticals for their generous gifts of bortezomib and MLN4924, Mark Smythe and Craig Crews for YU101, and Mei-Ling Kuo (City of Hope) for the p19ARF shRNA construct. We thank S. Materna for help with qPCR. We are grateful to A. Varshavsky and members of the Deshaies lab for critical reading of the manuscript. S.K.R. is supported by the multidisciplinary postdoctoral award (W81XWH-07-1-0641) from the Department of Defense Breast Cancer Research Program. P.Y. is supported by the Swedish Research Council and the Swedish Cancer Society. J.Y.C. and C.S.L. are supported by grants (CA091907 and NS065223) from the National Cancer Institute and National Institute of Neurological Disorders and Stroke. R.J.D. is an HHMI Investigator, and this work was supported in part by HHMI and Weston Havens Foundation. Stemming from founder's shares in Proteolix, R.J.D. retains rights to milestone payments from Onyx contingent upon FDA and EMEA approvals of carfilzomib.

Attached Files

Accepted Version - nihms-197198.pdf

Supplemental Material - mmc1.pdf


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