Thoma Claudio R, Toso Alberto, Gutbrodt Katrin L, Reggi Sabina P, Frew Ian J, Schraml Peter, Hergovich Alexander, Moch Holger, Meraldi Patrick, Krek Wilhelm
Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.
Nat Cell Biol. 2009 Aug;11(8):994-1001. doi: 10.1038/ncb1912. Epub 2009 Jul 20.
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.
无差错的有丝分裂依赖于保真度监测检查点系统，该系统通过微管纺锤体装置确保染色体分离在时间和空间上的正确协调。这些检查点系统的缺陷会导致基因组不稳定，这是肿瘤发生的一个重要方面。在这里，我们表明，在遗传性和散发性肾细胞癌中失活的冯·希佩尔-林道（VHL）肿瘤抑制蛋白pVHL定位于哺乳动物细胞的有丝分裂纺锤体，其功能失活会引发纺锤体方向错误、纺锤体检查点减弱和染色体不稳定。纺锤体方向错误与不稳定的星体微管有关，并且在pVHL缺陷细胞中野生型pVHL的恢复可抑制这种错误，但在微管稳定有缺陷的天然VHL病突变体中则不能。纺锤体检查点功能受损和染色体不稳定是由pVHL失活导致的Mad2（有丝分裂阻滞缺陷2）水平降低的结果，并且在VHL缺陷细胞中重新表达Mad2或pVHL可挽救这种情况。在人类肾癌中也发现了VHL失活、Mad2水平降低和非整倍体增加之间的关联，这意味着新发现的pVHL在促进正确纺锤体方向和染色体稳定性方面的功能可能有助于肿瘤抑制。
