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The ubiquitin-specific protease USP28 is required for MYC stability

Nature Cell Biology volume 9, pages 765–774 (2007)Cite this article

Abstract

The MYC proto-oncogene encodes a transcription factor that has been implicated in the genesis of many human tumours. Here, we used a bar-code short hairpin RNA (shRNA) screen to identify multiple genes that are required for MYC function. One of these genes encodes USP28, an ubiquitin-specific protease. USP28 is required for MYC stability in human tumour cells. USP28 binds to MYC through an interaction with FBW7α, an F-box protein that is part of an SCF-type ubiquitin ligase. Therefore, it stabilizes MYC in the nucleus, but not in the nucleolus, where MYC is degraded by FBW7γ. High expression levels of USP28 are found in colon and breast carcinomas, and stabilization of MYC by USP28 is essential for tumour-cell proliferation.

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Figure 1: A bar-code shRNA screen identifies USP28 as a gene required for MYC function.
Figure 2: Stabilization and deubiquitination of MYC by USP28.
Figure 3: USP28 antagonizes the function of FBW7.
Figure 4: USP28 binds to MYC via FBW7α.
Figure 5: Depletion of USP28 inhibits growth and proliferation via regulation of MYC protein levels.
Figure 6: Regulation of proliferation and differentiation of colon carcinoma cells by USP28.

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Acknowledgements

This study was supported by grants from the European Union (through the FP6 Integrated Project INTACT) to M.E. and R.B., the Deutsche Forschungsgemeinschaft (Forschergruppe Chromatin and Transregio17) to M.E. and the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NWO) to R.B. This work was supported by grants from the National Institutes of Health (NIH) and Cooperative Center for Medical Countermeasures Against Radiation (CMCR) to S.J.E. S.J.E. is a Howard Hughes Medical Institute Investigator. We thank D. Dobrin, B. Jebavy and R. Baumann for expert technical assistance, and M. Welcker and B. Clurman for FBW7 expression plasmids.

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Authors and Affiliations

  1. Institute of Molecular Biology and Tumor Research, Emil-Mannkopff-Str.2, Marburg, 35033, Germany

    Nikita Popov, Michael Wanzel & Martin Eilers

  2. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066, CX, Netherlands

    Mandy Madiredjo, Roderick Beijersbergen & Rene Bernards

  3. Department of Genetics, Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, MA, USA

    Dong Zhang & Stephen J. Elledge

  4. Department of Pathology, University of Marburg, Baldingerstrasse, 35033, Marburg, Germany

    Roland Moll

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Supplementary Figures S1, S2, S3, S4, Supplementary Tables T1, T2, T3, Supplementary Materials Methods and Supplementary Information (PDF 771 kb)

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Popov, N., Wanzel, M., Madiredjo, M. et al. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol 9, 765–774 (2007). https://doi.org/10.1038/ncb1601

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