Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation

Niels Mailand; Claudia Lukas; Brett K Kaiser; Peter K Jackson; Jiri Bartek; Jiri Lukas

doi:10.1038/ncb777

Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation

Niels Mailand, Claudia Lukas, Brett K Kaiser, Peter K Jackson, Jiri Bartek, Jiri Lukas

174 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Cell Biology
Vol/bind	4
Udgave nummer	4
Sider (fra-til)	317-22
Antal sider	6
ISSN	1465-7392
DOI	https://doi.org/10.1038/ncb777
Status	Udgivet - apr. 2002
Udgivet eksternt	Ja

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10.1038/ncb777

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title = "Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation",

abstract = "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.",

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author = "Niels Mailand and Claudia Lukas and Kaiser, {Brett K} and Jackson, {Peter K} and Jiri Bartek and Jiri Lukas",

year = "2002",

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doi = "10.1038/ncb777",

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T1 - Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation

AU - Mailand, Niels

AU - Lukas, Claudia

AU - Kaiser, Brett K

AU - Jackson, Peter K

AU - Bartek, Jiri

AU - Lukas, Jiri

PY - 2002/4

Y1 - 2002/4

N2 - 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.

AB - 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.

KW - Cell Cycle Proteins

KW - Cell Division

KW - Cell Line

KW - Cell Nucleus

KW - Centrosome

KW - Chromosomes

KW - Down-Regulation

KW - Flow Cytometry

KW - HeLa Cells

KW - Humans

KW - Immunoblotting

KW - Kinetics

KW - Microscopy, Fluorescence

KW - Microtubules

KW - Mitosis

KW - Mutation

KW - Phosphoric Monoester Hydrolases

KW - Plasmids

KW - Protein Tyrosine Phosphatases

KW - RNA

KW - Saccharomyces cerevisiae

KW - Saccharomyces cerevisiae Proteins

KW - Schizosaccharomyces

KW - Time Factors

KW - Transgenes

U2 - 10.1038/ncb777

DO - 10.1038/ncb777

M3 - Journal article

C2 - 11901424

SN - 1465-7392

VL - 4

SP - 317

EP - 322

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 4

ER -

Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation

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