VHL loss causes spindle misorientation and chromosome instability

Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.
Nature Cell Biology (Impact Factor: 20.06). 09/2009; 11(8):994-1001. DOI: 10.1038/ncb1912
Source: PubMed

ABSTRACT 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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Available from: Patrick Meraldi, Sep 02, 2015
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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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    ABSTRACT: Von Hippel-Lindau (VHL) syndrome is a hereditary condition predisposing to the development of different cancer forms, related to germline inactivation of the homonymous tumor suppressor pVHL. The best characterized function of pVHL is the ubiquitination dependent degradation of Hypoxia Inducible Factor (HIF) via the proteasome. It is also involved in several cellular pathways acting as a molecular hub and interacting with more than 200 different proteins. Molecular details of pVHL plasticity remain in large part unknown. Here, we present a novel manually curated Petri Net (PN) model of the main pVHL functional pathways. The model was built using functional information derived from the literature. It includes all major pVHL functions and is able to credibly reproduce VHL syndrome at the molecular level. The reliability of the PN model also allowed in silico knockout experiments, driven by previous model analysis. Interestingly, PN analysis suggests that the variability of different VHL manifestations is correlated with the concomitant inactivation of different metabolic pathways.
    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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    ABSTRACT: Hypoxia' or decreases in oxygen availability' results in the activation of a number of different responses at both the whole organism and the cellular level. These responses include drastic changes in gene expression, which allow the organism (or cell) to cope efficiently with the stresses associated with the hypoxic insult. A major breakthrough in the understanding of the cellular response to hypoxia was the discovery of a hypoxia sensitive family of transcription factors known as the hypoxia inducible factors (HIFs). The hypoxia response mounted by the HIFs promotes cell survival and energy conservation. As such, this response has to deal with important cellular process such as cell division. In this review, the integration of oxygen sensing with the cell cycle will be discussed. HIFs, as well as other components of the hypoxia pathway, can influence cell cycle progression. The role of HIF and the cell molecular oxygen sensors in the control of the cell cycle will be reviewed.
    Cellular and Molecular Life Sciences CMLS 05/2014; 71(18). DOI:10.1007/s00018-014-1645-9 · 5.86 Impact Factor
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    • "This implicates pVHL in the regulation of genes involved in cell proliferation and survival and in angiogenesis. In addition, pVHL exerts other functions that are completely independent of its role in HIFα degradation, including regulation of microtubule stabilization, cell cycle progression [8,10] maintenance of appropriate Mad2 protein levels and chromosomal stability [11]. "
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    ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer and is often characterized by mutations or deletions of the Von Hippel Lindau (VHL) tumour suppressor gene. Aurora gene family members are implicated in proper mitotic progression and spindle checkpoint function and play a crucial role in cancer progression. In the present study, we assessed the expression of Aurora-A in a cohort of 30 ccRCC with fully characterized VHL status (wt/wt or mut/del) and Fuhrman grade. Aurora-A transcript and protein levels were significantly increased in high Fuhrman grade tumours and in VHLwt/wt tumours. These results suggest that Aurora-A and VHL interact in the ccRCC. We demonstrated that the two proteins interact in vivo and identified the Ser72 on the sequence of VHL as the unique site phosphorylated by Aurora-A.
    PLoS ONE 06/2013; 8(6):e67071. DOI:10.1371/journal.pone.0067071 · 3.23 Impact Factor
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