Letter abstract
Nature Cell Biology 11, 994 - 1001 (2009)
Published online: 20 July 2009 | doi:10.1038/ncb1912
VHL loss causes spindle misorientation and chromosome instability
Claudio R. Thoma1,5, Alberto Toso2,5, Katrin L. Gutbrodt1, Sabina P. Reggi2, Ian J. Frew1, Peter Schraml3, Alexander Hergovich1,4, Holger Moch3, Patrick Meraldi2 & Wilhelm Krek1
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.
- Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.
- Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland.
- Institute for Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
- Current address: Friedrich Miescher Institute for Biomedical Research, 4002 Basel, Switzerland.
- These authors contributed equally to this work.
Correspondence to: Wilhelm Krek1 e-mail: wilhelm.krek@cell.biol.ethz.ch
Correspondence to: Patrick Meraldi2 e-mail: patrick.meraldi@bc.biol.ethz.ch
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