PMID:15311285

Citation	Krämer, A, Mailand, N, Lukas, C, Syljuåsen, RG, Wilkinson, CJ, Nigg, EA, Bartek, J and Lukas, J (2004) Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. Nat. Cell Biol. 6:884-91
Abstract	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.
Links	PubMed Online version:10.1038/ncb1165
Keywords	CDC2 Protein Kinase/metabolism; CDC2 Protein Kinase/physiology; Cell Cycle Proteins/physiology; Cell Division; Cell Line; Centrosome/enzymology; Cyclin B/metabolism; Cyclin B1; Cyclins/metabolism; Enzyme Activation; Humans; Interphase; Microscopy, Confocal; Mitotic Spindle Apparatus; Protein Binding; Protein Kinases/metabolism; Protein Kinases/physiology; cdc25 Phosphatases/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:CHK1	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:CHK1	part_of	GO:0005813: centrosome	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:CHK1	involved_in	GO:0045839: negative regulation of mitotic nuclear division	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:CHK1	involved_in	GO:0046602: regulation of mitotic centrosome separation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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