Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation.
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.
Mailand
Niels
N
Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Lukas
Claudia
C
Kaiser
Brett K
BK
Jackson
Peter K
PK
Bartek
Jiri
J
Lukas
Jiri
J
D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism* / Q000648:ultrastructure; D002875:Chromosomes / Q000648:ultrastructure*; D015536:Down-Regulation; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000648:ultrastructure; D008938:Mitosis; D009154:Mutation; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases; D012313:RNA / Q000648:ultrastructure; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D012568:Schizosaccharomyces / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes
C074860:CDC14 protein, S cerevisiae; D018797:Cell Cycle Proteins; D029701:Saccharomyces cerevisiae Proteins; D012313:RNA; D010744:Phosphoric Monoester Hydrolases; C120902:CDC14A protein, human; D017027:Protein Tyrosine Phosphatases