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Protective function of von Hippel-Lindau protein against impaired protein processing in renal carcinoma cells
1Laboratory of Biological Chemistry, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. myriam-gorospe@nih.gov
Abstract:
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.
Insights
Von Hippel-Lindau (VHL) gene deficiency increases renal cell carcinoma (RCC) sensitivity to glucose deprivation. VHL-deficient cells struggle to process misfolded proteins, impacting cell survival under stress.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Stress Response
Background:
- Von Hippel-Lindau (VHL) disease is linked to VHL tumor suppressor gene loss, causing specific neoplasias like renal cell carcinoma (RCC).
- Understanding VHL's role in cellular stress response is crucial for VHL disease and RCC pathogenesis.
Purpose of the Study:
- To compare the stress sensitivity of VHL-deficient RCC cells versus wild-type VHL (wtVHL) expressing RCC cells.
- To investigate the mechanisms underlying differential sensitivity, particularly concerning protein processing and degradation.
Main Methods:
- Exposure of VHL-deficient and wtVHL RCC cells to various stresses, including glucose deprivation and protein processing inhibitors (tunicamycin, brefeldin A, azetidine).
- Assessment of cellular cytotoxicity, glucose uptake, energy metabolism, protein ubiquitination, and protein degradation rates.
Main Results:
- VHL-deficient RCC cells exhibited significantly higher sensitivity to glucose deprivation compared to wtVHL cells.
- This heightened sensitivity was not due to altered energy metabolism or glucose uptake but linked to impaired handling of misfolded proteins.
- Treatments interfering with protein processing and elevated protein ubiquitination were more toxic to VHL-deficient cells, indicating a role for VHL in proteolysis.
Conclusions:
- The VHL gene product (pVHL) plays a role in eliminating misprocessed proteins, particularly under conditions of glucose deprivation or other cellular stresses.
- VHL deficiency compromises the ubiquitin-proteasome system's ability to clear aberrant proteins, contributing to cellular vulnerability.