title: Chk1 is required for spindle checkpoint function.
abstract: The spindle checkpoint delays anaphase onset in cells with mitotic spindle defects. Here, we show that Chk1, a component of the DNA damage and replication checkpoints, protects vertebrate cells against spontaneous chromosome missegregation and is required to sustain anaphase delay when spindle function is disrupted by taxol, but not when microtubules are completely depolymerized by nocodazole. Spindle checkpoint failure in Chk1-deficient cells correlates with decreased Aurora-B kinase activity and impaired phosphorylation and kinetochore localization of BubR1. Furthermore, Chk1 phosphorylates Aurora-B and enhances its catalytic activity in vitro. We propose that Chk1 augments spindle checkpoint signaling and is required for optimal regulation of Aurora-B and BubR1 when kinetochores produce a weakened signal. In addition, Chk1-deficient cells exhibit increased resistance to taxol. These results suggest a mechanism through which Chk1 could protect against tumorigenesis through its role in spindle checkpoint signaling.
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom. g.zachos@beatson.gla.ac.uk
authors.forename: George
authors.initials: G
authors.lastname: Zachos
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Black
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Mary T
authors.initials: MT
authors.lastname: Scott
authors.forename: Paola
authors.initials: P
authors.lastname: Vagnarelli
authors.forename: William C
authors.initials: WC
authors.lastname: Earnshaw
authors.forename: David A F
authors.initials: DA
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001704:Biopolymers / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D002645:Chickens; D043171:Chromosomal Instability / Q000187:drug effects / Q000235:genetics; D020090:Chromosome Segregation / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D018386:Kinetochores / Q000187:drug effects / Q000201:enzymology; D008870:Microtubules / Q000187:drug effects / Q000201:enzymology; D009369:Neoplasms / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D049468:Prometaphase / Q000187:drug effects; D011494:Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects / Q000201:enzymology*
chemical_list: D001704:Biopolymers; D011494:Protein Kinases; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel