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Originally published In Press as doi:10.1074/jbc.M109023200 on October 11, 2001

J. Biol. Chem., Vol. 276, Issue 49, 46073-46078, December 7, 2001
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Sensitivity of Mammalian Cells Expressing Mutant Ubiquitin to Protein-damaging Agents*

Maria TsirigotisDagger §, Mei ZhangDagger , Roland K. ChiuDagger ||, Bradly G. WoutersDagger ||, and Douglas A. GrayDagger **Dagger Dagger

From the Dagger  Ottawa Regional Cancer Centre, Ottawa, Ontario K1H 1C4 and the Departments of § Biochemistry, Microbiology, and Immunology and ** Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

There is convincing evidence from studies in yeast that a functional ubiquitin/proteasome pathway is required to degrade misfolded or oxidatively damaged proteins but for technical reasons, it has been difficult to perform comparable studies in mammalian cells. To investigate the possibility that the ubiquitin/proteasome pathway is cytoprotective for mammalian cells, we have introduced epitope-tagged wild-type ubiquitin or dominant-negative mutant versions of ubiquitin into mouse HT4 neuroblastoma cells. Cells expressing mutant versions of ubiquitin were found to be sensitive to cadmium, an agent that causes oxidative damage to cellular components, and to canavanine, an amino acid analog that generates misfolded proteins. The greatest sensitivity to canavanine was observed in cells expressing a mutant version of ubiquitin unable to support the formation of Lys48 linkages. Substrates of the proteasome were found to accumulate in these cells, suggesting a general deficit in proteolysis. Our data suggest that defects in the ubiquitin-mediated proteolytic system predispose mammalian cells to the toxic effects of abnormal protein.

* The work was supported by Grant MT-15134 from the Canadian Institutes of Health Research (to D. A. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of an Ontario graduate scholarship in science and technology.

|| Present address: Dept. of Radiation Oncology, University of Maastricht, 6200 MD Maastricht, The Netherlands.

Dagger Dagger To whom correspondence should be addressed: Centre for Cancer Therapeutics, Ottawa Regional Cancer Centre, 503 Smyth Rd., Ottawa, Ontario K1H 1C4, Canada. Tel.: 613-737-7700 (ext. 6896); Fax: 613-247-3524; E-mail: Doug.Gray@orcc.on.ca.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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