Chk1-dependent regulation of Cdc25B functions to coordinate mitotic events.
The coordination of mitotic spindle formation and chromatin condensation is an essential prerequisite for successful mitosis. Both events are thought to be initiated by cyclin B/Cdk1, whose initial activation occurs in late prophase at the centrosomes. Recently, we have shown that Chk1 localizes to interphase centrosomes and thereby negatively regulates entry into mitosis by preventing premature activation of cyclin B/Cdk1. Here, we demonstrate that inhibition of Chk1 kinase induces mitotic entry with regular spindle assembly but aberrant and mislocalized chromatin. This effect, which we have termed the 'paraspindle' phenotype, was reverted by downregulation of Cdc25B phosphatase using siRNA, which restored normal mitosis with regular chromatin. Analogous to Chk1 inhibition, the 'paraspindle' phenotype was induced by overexpression of Cdc25B but not Cdc25A. Our results suggest that Chk1 functions to coordinate mitotic events through regulation of Cdc25B.
Löffler
Harald
H
Clinical Cooperation Unit for Molecular Hematology/Oncology, German Cancer Research Center (DKFZ).
Rebacz
Blanka
B
Ho
Anthony D
AD
Lukas
Jiri
J
Bartek
Jiri
J
Krämer
Alwin
A
D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis; D008954:Models, Biological; D010641:Phenotype; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D008941:Spindle Apparatus; D013997:Time Factors; D020687:cdc25 Phosphatases / Q000378:metabolism / Q000502:physiology*
D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C517004:CDC25A protein, human; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases