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PMID:15311285

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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

Significance

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


See also

References

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