VHL loss causes spindle misorientation and chromosome instability

Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.
Nature Cell Biology (Impact Factor: 19.68). 09/2009; 11(8):994-1001. DOI: 10.1038/ncb1912
Source: PubMed


Error-free mitosis depends on fidelity-monitoring checkpoint systems that ensure correct temporal and spatial coordination of chromosome segregation by the microtubule spindle apparatus. Defects in these checkpoint systems can lead to genomic instability, an important aspect of tumorigenesis. Here we show that the von Hippel-Lindau (VHL) tumour suppressor protein, pVHL, which is inactivated in hereditary and sporadic forms of renal cell carcinoma, localizes to the mitotic spindle in mammalian cells and its functional inactivation provokes spindle misorientation, spindle checkpoint weakening and chromosomal instability. Spindle misorientation is linked to unstable astral microtubules and is supressed by the restoration of wild-type pVHL in pVHL-deficient cells, but not in naturally-occurring VHL disease mutants that are defective in microtubule stabilization. Impaired spindle checkpoint function and chromosomal instability are the result of reduced Mad2 (mitotic arrest deficient 2) levels actuated by pVHL-inactivation and are rescued by re-expression of either Mad2 or pVHL in VHL-defective cells. An association between VHL inactivation, reduced Mad2 levels and increased aneuploidy was also found in human renal cancer, implying that the newly identified functions of pVHL in promoting proper spindle orientation and chromosomal stability probably contribute to tumour suppression.

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    • "DeMAND successfully identified the known high-affinity target of vincristine (TUBB), as well as CCNB1, VHL, RPS3A, and NFKBIA, in the top five predictions. While RPS3A and VHL are known to affect mitotic spindle assembly (Jang et al., 2012; Thoma et al., 2009), and CCNB1 is a microtubule activity marker, their function in mediating/modulating vincristine's activity is unknown. Probing the microtubule network with an anti-tubulin antibody, following small interfering RNA (siRNA)-mediated silencing of these genes, confirmed that loss of RPS3A (but not of VHL, CCNB1, or NFKBIA) disrupts microtubules in adherent U-2-OS cells (Figure 3A). "
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    ABSTRACT: Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small-molecule MoA and compound similarity. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 07/2015; 162(2):441-451. DOI:10.1016/j.cell.2015.05.056 · 32.24 Impact Factor
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    • "Indeed, pVHL was found in different cellular compartments and seems to be involved in many different cellular processes such as apoptosis, cell proliferation, survival and motility [26]. Considering the huge number of interactors and multiple cellular localizations, many different functions have been described or hypothesized, such as regulation of cytoplasmic microtubules during mitosis [27] and endothelial extracellular matrix deposition [28]. On the other hand, considering the huge number of players involved in VHL syndrome and the lack of reliable kinetic data, a PN based approach may be a preferable option for an entire VHL pathway simulation. "
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    PLoS ONE 06/2014; 9(6):e96986. DOI:10.1371/journal.pone.0096986 · 3.23 Impact Factor
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    • "However, more recently, VHL has also been shown to regulate mitotic spindle. In a study by Krek and colleagues, it was shown that VHL localizes to mitotic spindle in human cells [114]. Loss of function of VHL was shown to lead to spindle and spindle checkpoint defects that ultimately control chromosome instability. "
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