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Transcription Factor Nrf1 Mediates the Proteasome Recovery Pathway after Proteasome Inhibition in Mammalian Cells
Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
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2010 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 38, no 1, 17-28 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2010. Vol. 38, no 1, 17-28 p.
National Category
Biological Sciences
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-52207DOI: 10.1016/j.molcel.2010.02.029ISI: 000276627800004OAI: oai:DiVA.org:su-52207DiVA: diva2:387429
Note
authorCount :6Available from: 2011-01-14 Created: 2011-01-13 Last updated: 2017-12-11Bibliographically approved
In thesis
1. The Path to Destruction: Understanding the mechanism and regulation of proteasomal degradation
Open this publication in new window or tab >>The Path to Destruction: Understanding the mechanism and regulation of proteasomal degradation
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A majority of intracellular proteins are degraded by the ubiquitin proteasome system (UPS). In this thesis, both the mechanism of the degradation and the regulation of UPS have been investigated. The importance of the p97 ATPase for proteasomal degradation of cytosolic substrates was examined. It was shown that tightly folded model substrates were dependent on p97 for their degradation. In addition to this, it was shown that an extended flexible peptide sequence on the substrate allowed degradation to occur directly by the proteasome. We propose that p97 works as an unfoldase on substrates that lack initiation regions. These results were originally achieved with experiments using Drosophila melanogaster S2 cell culture. Corresponding experiments were carried out in human cell lines. We observed that the human proteasome also needed assistance from the human p97 protein complex when model substrates lacked unfolded tagged regions. To identify the transcription factor(s) that regulate the expression of proteasomal genes, a large scale RNAi screen was performed. A library consisting of dsRNA to all known and predicted transcription factors in Drosophila was used. Drosophila S2 cells expressing the cytosolic UbG76V-GFP substrate were used in the screen. Since thisfusion protein isdependent on the UPS for its degradation,failure in UPS can easily be detected viafluorescent stabilization.When dsRNA targeted the bZIP transcription factor Cnc-C,it lead to a reduction of the proteasome subunit protein levels as well as decreased mRNA levels. Phylogenetic analysis together with sequence alignments were used to learn how Cnc-C is related to the bZIP CNC genes in other metazoans and in particular mammalian cells. In mammalian cells, NF-E2, Nrf1, Nrf2 and Nrf3 are present and we propose that Cnc-C is related to a common ancestor transcription factor for all these four genes. This contradicts earlier studies proposing that Cnc-C is a homolog of the mammalian Nrf2 protein.In the last study, theproteasome recovery pathway was examined tounderstand which bZIPtranscription factor in human cells is responsible for the expression of proteasome genes after proteasome inhibition.Different cancer cell lines were used to examine theexpression level of proteasome genes after treating the cells with proteasome inhibitors when either the bZIP protein Nrf1 or Nrf2 wereknocked down. It was shown that Nrf1-/- cellslacked the ability toupregulate proteasome genes after proteasomeinhibition. In contrast, Nrf2-/- cells still had the capacity to restore proteasome levels. This lead to the conclusion thatNrf1 is responsible for the proteasome recovery pathway in mammalian cells.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biology and Functional Genomics, Stockholm University, 2011. 65 p.
Keyword
Proteasome, ubiquitin, p97, Cnc-C, transcription factors, Nrf1, Nrf2
National Category
Biological Sciences
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-63762 (URN)978-91-7447-384-1 (ISBN)
Public defence
2011-12-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
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Available from: 2011-11-10 Created: 2011-10-28 Last updated: 2013-12-06Bibliographically approved

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