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c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells

Nature Cell Biology volume 3, pages 283–288 (2001)Cite this article

Abstract

Burkitt's lymphoma (BL) is a highly malignant B-cell tumour characterized by chromosomal translocations that constitutively activate the c-myc oncogene. Here we show that BL cells are resistant to apoptosis and do not accumulate ubiquitin conjugates in response to otherwise toxic doses of inhibitors of the proteasome. Deubiquitinating enzymes and the cytosolic subtilisin-like protease tripeptidylpeptidase II are upregulated in BLs, and could be rapidly induced by the overexpression of c-myc in normal B cells carrying oestrogen-driven recombinant Epstein–Barr virus. Apoptosis was induced by inhibiting tripeptidylpeptidase II, suggesting that the activity of this protease may be required for the survival of BL cells. We thus show that there is a regulatory link between c-myc activation and changes in proteolysis that may affect malignant transformation.

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Figure 1: BL cells are resistant to induction of apoptosis by inhibitors of the proteasome.
Figure 2: Protein turnover is not affected by inhibition of the proteasome in BL cells.
Figure 3: BL cells fail to accumulate ubiquitin conjugates on inhibition of the proteasome.
Figure 4: Deubiquitinating enzymes are upregulated in BL cells.
Figure 5: TPPII is upregulated in BL cells.
Figure 6: An alternative proteolytic pathway is required for BL cell survival.

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Acknowledgements

We thank H. Ploegh and B. Tomkinson for the NLVS and butabindide, and members of the Masucci laboratory for helpful discussions and critically reading the manuscript. This work was supported by grants from the Swedish Cancer Society, the Swedish Foundation of Strategy Research and the Petrus and Augusta Hedlund Foundation, Stockholm, Sweden, and by the DFG. S.V. was supported by a fellowship from the European Commission Training and Mobility Program on `The central role of the ubiquitin proteasome system in regulatory processes involved in immunological, inflammatory, endocrinological and malignant disorders'.

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  1. Riccardo Gavioli and Teresa Frisan: These authors contributed equally to this work

Authors and Affiliations

  1. Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, Stockholm, S-171 77, Sweden

    Riccardo Gavioli, Teresa Frisan, Simona Vertuani & Maria G. Masucci

  2. Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, 44100, Italy

    Riccardo Gavioli & Simona Vertuani

  3. GSF Research Centre for Environment and Health, Institute of Molecular Biology and Tumor Genetics, Marchioninistrasse 25, Munich, D-81377, Germany

    Georg W. Bornkamm

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  1. Riccardo Gavioli
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Correspondence to Maria G. Masucci.

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Gavioli, R., Frisan, T., Vertuani, S. et al. c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells. Nat Cell Biol 3, 283–288 (2001). https://doi.org/10.1038/35060076

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