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Von Hippel-Lindau gene product directs cytokinesis: a new tumor suppressor function
Sutapa Sinha1, Gourish Mondal, Eun Ju Hwang
1Department of Biochemistry and Molecular Biology, Mayo Clinic Foundation, Rochester, MN 55905, USA.
Abstract:
One of the mechanisms of tumorigenesis is that the failure of cell division results in genetically unstable, multinucleated cells. Here we show that pVHL, a tumor suppressor protein that has been implicated in the pathogenesis of renal cell carcinoma (RCC), plays an important role in regulation of cytokinesis. We found that pVHL-deficient RCC 786-O cells were multinucleated and polyploid. Reintroduction of wild-type pVHL into these cells rescued the diploid cell population, whereas the mutant pVHL-K171G failed to do so. We demonstrate that lysine 171 of pVHL is important for the final step of cytokinesis: the midbody abscission. The pVHL-K171G caused failure to localize the ESCRT-1 interacting protein Alix and the v-SNARE complex component Endobrevin to the midbody in 786-O cells, leading to defective cytokinesis. Moreover, SUMOylation of pVHL at lysine 171 might modulate its function as a cytokinesis regulator. pVHL tumor suppressor function was also disrupted by the K171G mutation, as evidenced by the xenograft tumor formation when 786-O clones expressing pVHL-K171G were injected into mice. Most RCC cell lines show a polyploid chromosome complement and consistent heterogeneity in chromosome number. Thus, this study offers a way to explain the chromosome instability in RCC and reveals a new direction for the tumor suppressor function of pVHL, which is independent of its E3 ubiquitin ligase activity.
Insights
The tumor suppressor pVHL regulates cell division (cytokinesis), and its deficiency causes multinucleated cells in renal cell carcinoma (RCC). A specific mutation (K171G) disrupts this function, leading to chromosome instability and tumor formation.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Tumorigenesis can arise from failed cell division, producing genetically unstable, multinucleated cells.
- The tumor suppressor protein pVHL is linked to renal cell carcinoma (RCC) pathogenesis.
Purpose of the Study:
- To investigate the role of pVHL in regulating cytokinesis.
- To elucidate the mechanism by which pVHL deficiency contributes to RCC development and chromosome instability.
Main Methods:
- Analysis of pVHL-deficient RCC 786-O cells and reintroduction of wild-type and mutant pVHL.
- Assessment of cell ploidy, multinucleation, and localization of cytokinesis-related proteins (Alix, Endobrevin).
- Xenograft tumor formation studies in mice to evaluate pVHL's tumor suppressor function.
Main Results:
- pVHL-deficient cells exhibited multinucleation and polyploidy, which were rescued by wild-type pVHL but not by the K171G mutant.
- The pVHL K171G mutation impaired midbody abscission by preventing the localization of Alix and Endobrevin, leading to defective cytokinesis.
- pVHL's tumor suppressor activity was compromised by the K171G mutation, as shown by increased tumor formation in vivo.
Conclusions:
- Lysine 171 of pVHL is critical for the final step of cytokinesis (midbody abscission) and its proper regulation.
- pVHL's role in maintaining chromosome stability is independent of its E3 ubiquitin ligase activity, offering new insights into its tumor suppressor function in RCC.
- SUMOylation of pVHL at lysine 171 may modulate its function in cytokinesis regulation.
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