Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase
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Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. / Krämer, Alwin; Mailand, Niels; Lukas, Claudia; Syljuåsen, Randi G; Wilkinson, Christopher J; Nigg, Erich A; Bartek, Jiri; Lukas, Jiri.
In: Nature Cell Biology, Vol. 6, No. 9, 09.2004, p. 884-91.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase
AU - Krämer, Alwin
AU - Mailand, Niels
AU - Lukas, Claudia
AU - Syljuåsen, Randi G
AU - Wilkinson, Christopher J
AU - Nigg, Erich A
AU - Bartek, Jiri
AU - Lukas, Jiri
PY - 2004/9
Y1 - 2004/9
N2 - Entry into mitosis occurs after activation of Cdk1, resulting in chromosome condensation in the nucleus and centrosome separation, as well as increased microtubule nucleation activity in the cytoplasm. The active cyclin-B1-Cdk1 complex first appears at the centrosome, suggesting that the centrosome may facilitate the activation of mitotic regulators required for the commitment of cells to mitosis. However, the signalling pathways involved in controlling the initial activation of Cdk1 at the centrosome remain largely unknown. Here, we show that human Chk1 kinase localizes to interphase, but not mitotic, centrosomes. Chemical inhibition of Chk1 resulted in premature centrosome separation and activation of centrosome-associated Cdk1. Forced immobilization of kinase-inactive Chk1 to centrosomes also resulted in premature Cdk1 activation. Conversely, under such conditions wild-type Chk1 impaired activation of centrosome-associated Cdk1, thereby resulting in DNA endoreplication and centrosome amplification. Activation of centrosomal Cdk1 in late prophase seemed to be mediated by cytoplasmic Cdc25B, whose activity is controlled by centrosome-associated Chk1. These results suggest that centrosome-associated Chk1 shields centrosomal Cdk1 from unscheduled activation by cytoplasmic Cdc25B, thereby contributing to proper timing of the initial steps of cell division, including mitotic spindle formation.
AB - Entry into mitosis occurs after activation of Cdk1, resulting in chromosome condensation in the nucleus and centrosome separation, as well as increased microtubule nucleation activity in the cytoplasm. The active cyclin-B1-Cdk1 complex first appears at the centrosome, suggesting that the centrosome may facilitate the activation of mitotic regulators required for the commitment of cells to mitosis. However, the signalling pathways involved in controlling the initial activation of Cdk1 at the centrosome remain largely unknown. Here, we show that human Chk1 kinase localizes to interphase, but not mitotic, centrosomes. Chemical inhibition of Chk1 resulted in premature centrosome separation and activation of centrosome-associated Cdk1. Forced immobilization of kinase-inactive Chk1 to centrosomes also resulted in premature Cdk1 activation. Conversely, under such conditions wild-type Chk1 impaired activation of centrosome-associated Cdk1, thereby resulting in DNA endoreplication and centrosome amplification. Activation of centrosomal Cdk1 in late prophase seemed to be mediated by cytoplasmic Cdc25B, whose activity is controlled by centrosome-associated Chk1. These results suggest that centrosome-associated Chk1 shields centrosomal Cdk1 from unscheduled activation by cytoplasmic Cdc25B, thereby contributing to proper timing of the initial steps of cell division, including mitotic spindle formation.
KW - CDC2 Protein Kinase
KW - Cell Cycle Proteins
KW - Cell Division
KW - Cell Line
KW - Centrosome
KW - Cyclin B
KW - Cyclin B1
KW - Cyclins
KW - Enzyme Activation
KW - Humans
KW - Interphase
KW - Microscopy, Confocal
KW - Protein Binding
KW - Protein Kinases
KW - Spindle Apparatus
KW - cdc25 Phosphatases
U2 - 10.1038/ncb1165
DO - 10.1038/ncb1165
M3 - Journal article
C2 - 15311285
VL - 6
SP - 884
EP - 891
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 9
ER -
ID: 124903882