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VHL loss causes spindle misorientation and chromosome instability

Thoma, Claudio R. and Toso, Alberto and Gutbrodt, Katrin L. and Reggi, Sabina P. and Frew, Ian J. and Schraml, Peter and Hergovich, Alexander and Moch, Holger and Meraldi, Patrick and Krek, Wilhelm. (2009) VHL loss causes spindle misorientation and chromosome instability. Nature cell biology, Vol. 11. pp. 994-1001.

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Official URL: http://edoc.unibas.ch/dok/A6003949

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
UniBasel Contributors:Schraml, Peter Hans
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:MacMillan
ISSN:1465-7392
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:21
Deposited On:24 May 2013 09:00

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