Mailand Niels, Lukas Claudia, Kaiser Brett K, Jackson Peter K, Bartek Jiri, Lukas Jiri
Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Nat Cell Biol. 2002 Apr;4(4):317-22. doi: 10.1038/ncb777.
We show that human Cdc14A phosphatase interacts with interphase centrosomes, and that this interaction is independent of microtubules and Cdc14A phosphatase activity, but requires active nuclear export. Disrupting the nuclear export signal (NES) led to Cdc14A being localized in nucleoli, which in unperturbed cells selectively contain Cdc14B (ref. 1). Conditional overproduction of Cdc14A, but not its phosphatase-dead or NES-deficient mutants, or Cdc14B, resulted in premature centrosome splitting and formation of supernumerary mitotic spindles. In contrast, downregulation of endogenous Cdc14A by short inhibitory RNA duplexes (siRNA) induced mitotic defects including impaired centrosome separation and failure to undergo productive cytokinesis. Consequently, both overexpression and downregulation of Cdc14A caused aberrant chromosome partitioning into daughter cells. These results indicate that Cdc14A is a physiological regulator of the centrosome duplication cycle, which, when disrupted, can lead to genomic instability in mammalian cells.
我们发现人类Cdc14A磷酸酶与间期中心体相互作用，且这种相互作用独立于微管和Cdc14A磷酸酶活性，但需要活跃的核输出。破坏核输出信号（NES）会导致Cdc14A定位于核仁，而在未受干扰的细胞中，核仁选择性地含有Cdc14B（参考文献1）。Cdc14A的条件性过量表达，而非其磷酸酶失活或NES缺陷型突变体，或Cdc14B的过量表达，会导致中心体过早分裂和形成多余的有丝分裂纺锤体。相反，通过短干扰RNA双链体（siRNA）下调内源性Cdc14A会诱导有丝分裂缺陷，包括中心体分离受损和无法进行有效的胞质分裂。因此，Cdc14A的过表达和下调都会导致异常的染色体分配到子细胞中。这些结果表明，Cdc14A是中心体复制周期的生理调节因子，当其受到破坏时，可导致哺乳动物细胞中的基因组不稳定。
