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Molecular and Cellular Biology, February 1999, p. 1289-1300, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Protective Function of von Hippel-Lindau Protein against Impaired Protein Processing in Renal Carcinoma Cells

Myriam Gorospe,1,* Josephine M. Egan,2 Berton Zbar,3 Michael Lerman,3 Laura Geil,4 Igor Kuzmin,4 and Nikki J. Holbrook1

Laboratory of Biological Chemistry,1 Laboratory of Clinical Physiology,2 National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, and Laboratory of Immunobiology3 and Intramural Research Support Program,4 SAIC-Frederick, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702

Received 7 June 1998/Returned for modification 14 August 1998/Accepted 2 November 1998

The absence of functional von Hippel-Lindau (VHL) tumor suppressor gene leads to the development of neoplasias characteristic of VHL disease, including renal cell carcinoma (RCC). Here, we compared the sensitivity of RCC cells lacking VHL gene function with that of RCC cells expressing the wild-type VHL gene (wtVHL) after exposure to various stresses. While the response to most treatments was not affected by the VHL gene status, glucose deprivation was found to be much more cytotoxic for RCC cells lacking VHL gene function than for wtVHL-expressing cells. The heightened sensitivity of VHL-deficient cells was not attributed to dissimilar energy requirements or to differences in glucose uptake, but more likely reflects a lesser ability of VHL-deficient cells to handle abnormally processed proteins arising from impaired glycosylation. In support of this hypothesis, other treatments which act through different mechanisms to interfere with protein processing (i.e., tunicamycin, brefeldin A, and azetidine) were also found to be much more toxic for VHL-deficient cells. Furthermore, ubiquitination of cellular proteins was elevated in VHL-deficient cells, particularly after glucose deprivation, supporting a role for the VHL gene in ubiquitin-mediated proteolysis. Accordingly, the rate of elimination of abnormal proteins was lower in cells lacking a functional VHL gene than in wtVHL-expressing cells. Thus, pVHL appears to participate in the elimination of misprocessed proteins, such as those arising in the cell due to the unavailability of glucose or to other stresses.

* Corresponding author. Mailing address: Box 12, Laboratory of Biological Chemistry, GRC, National Institute on Aging, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825. Phone: (410) 558-8197. Fax: (410) 558-8335. E-mail: myriam-gorospe{at}nih.gov.

Molecular and Cellular Biology, February 1999, p. 1289-1300, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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