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PMID: 17276342 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Chk1 is required for spindle checkpoint function.

Developmental cell ·Vol. 12 ·No. 2 ·2007-02-00 ·Pages 247-60

Zachos G, Black EJ, Walker M, Scott MT, Vagnarelli P, Earnshaw WC, Gillespie DA

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.

MeSH Terms
Animals Aurora Kinase B Aurora Kinases Biopolymers/metabolism Catalysis/drug effects Cell Death/drug effects Checkpoint Kinase 1 Chickens Chromosomal Instability/drug effects,genetics Chromosome Segregation/drug effects,genetics HCT116 Cells Humans Kinetochores/drug effects,enzymology Microtubules/drug effects,enzymology Neoplasms/pathology Paclitaxel/pharmacology Phosphorylation/drug effects Prometaphase/drug effects Protein Kinases/deficiency,metabolism Protein Serine-Threonine Kinases/metabolism Protein Transport/drug effects Spindle Apparatus/drug effects,enzymology
Chemicals
Biopolymers Protein Kinases AURKB protein, human Aurora Kinase B Aurora Kinases BUB1 protein, human Bub1 spindle checkpoint protein CHEK1 protein, human Checkpoint Kinase 1 Protein Serine-Threonine Kinases Paclitaxel
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Zachos George
Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom. g.zachos@beatson.gla.ac.uk
Black Elizabeth J
Walker Mark
Scott Mary T
Vagnarelli Paola
Earnshaw William C
Gillespie David A F
References (37)
37 references, click to expand
  1. The Xenopus Chk1 protein kinase mediates a caffeine-sensitive pathway of checkpoint control in cell-free extracts.
    J Cell Biol. 1998 Sep 21;142(6):1559-69 PMID: 9744884
  2. Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability.
    Cancer Cell. 2003 Dec;4(6):483-97 PMID: 14706340
  3. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.
    Nat Med. 2004 Mar;10(3):262-7 PMID: 14981513
  4. Drosophila Wee1 kinase regulates Cdk1 and mitotic entry during embryogenesis.
    Curr Biol. 2004 Dec 14;14(23):2143-8 PMID: 15589158
  5. Mitotic forces control a cell-cycle checkpoint.
    Nature. 1995 Feb 16;373(6515):630-2 PMID: 7854422
  6. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01.
    J Biol Chem. 2000 Feb 25;275(8):5600-5 PMID: 10681541
  7. Localization of Mad2 to kinetochores depends on microtubule attachment, not tension.
    J Cell Biol. 1998 Jun 1;141(5):1181-91 PMID: 9606210
  8. The Drosophila Grp/Chk1 DNA damage checkpoint controls entry into anaphase.
    Curr Biol. 2005 Feb 22;15(4):334-9 PMID: 15723794
  9. The budding yeast protein kinase Ipl1/Aurora allows the absence of tension to activate the spindle checkpoint.
    Genes Dev. 2001 Dec 1;15(23):3118-29 PMID: 11731476
  10. On the road to cancer: aneuploidy and the mitotic checkpoint.
    Nat Rev Cancer. 2005 Oct;5(10):773-85 PMID: 16195750
  11. Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p.
    Cell. 2002 Oct 18;111(2):163-72 PMID: 12408861
  12. Taxol stabilizes microtubules in mouse fibroblast cells.
    Proc Natl Acad Sci U S A. 1980 Mar;77(3):1561-5 PMID: 6103535
  13. Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis.
    Mol Biol Cell. 2003 Aug;14(8):3325-41 PMID: 12925766
  14. Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death.
    EMBO J. 1998 Jan 15;17(2):598-608 PMID: 9430650
  15. The fission yeast Crb2/Chk1 pathway coordinates the DNA damage and spindle checkpoint in response to replication stress induced by topoisomerase I inhibitor.
    Mol Cell Biol. 2005 Sep;25(17):7889-99 PMID: 16107732
  16. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores.
    J Cell Biol. 2003 Apr 28;161(2):267-80 PMID: 12719470
  17. Chk1-dependent S-M checkpoint delay in vertebrate cells is linked to maintenance of viable replication structures.
    Mol Cell Biol. 2005 Jan;25(2):563-74 PMID: 15632059
  18. Chk1-deficient tumour cells are viable but exhibit multiple checkpoint and survival defects.
    EMBO J. 2003 Feb 3;22(3):713-23 PMID: 12554671
  19. Tension on chromosomes increases the number of kinetochore microtubules but only within limits.
    J Cell Sci. 2000 Nov;113 Pt 21:3815-23 PMID: 11034909
  20. Lack of tension at kinetochores activates the spindle checkpoint in budding yeast.
    Curr Biol. 2001 Sep 18;11(18):1462-7 PMID: 11566107
  21. Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints.
    Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4492-7 PMID: 11274370
  22. Autophosphorylation of a newly identified site of Aurora-B is indispensable for cytokinesis.
    J Biol Chem. 2004 Mar 26;279(13):12997-3003 PMID: 14722118
  23. Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice.
    Genes Dev. 2000 Jun 15;14(12):1439-47 PMID: 10859163
  24. Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase.
    Nat Cell Biol. 2004 Sep;6(9):884-91 PMID: 15311285
  25. Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP) by the Aurora B Kinase stimulates Aurora B kinase activity.
    J Biol Chem. 2002 Aug 2;277(31):27577-80 PMID: 12048181
  26. Regulation of mitotic function of Chk1 through phosphorylation at novel sites by cyclin-dependent kinase 1 (Cdk1).
    Genes Cells. 2006 May;11(5):477-85 PMID: 16629900
  27. TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68.
    J Biol Chem. 2005 Mar 4;280(9):7748-57 PMID: 15618221
  28. Checkpoint kinase 1 (Chk1) is required for mitotic progression through negative regulation of polo-like kinase 1 (Plk1).
    Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11964-9 PMID: 16873548
  29. Chk1-dependent regulation of Cdc25B functions to coordinate mitotic events.
    Cell Cycle. 2006 Nov 1;5(21):2543-7 PMID: 17106257
  30. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.
    Science. 1997 Sep 5;277(5331):1501-5 PMID: 9278512
  31. Timing and checkpoints in the regulation of mitotic progression.
    Dev Cell. 2004 Jul;7(1):45-60 PMID: 15239953
  32. Survivin is required for stable checkpoint activation in taxol-treated HeLa cells.
    J Cell Sci. 2003 Jul 15;116(Pt 14):2987-98 PMID: 12783991
  33. Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation.
    J Biol Chem. 2003 Apr 25;278(17):14806-11 PMID: 12588868
  34. The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments.
    Nat Cell Biol. 2005 Jan;7(1):93-8 PMID: 15592459
  35. The human kinetochore proteins Nnf1R and Mcm21R are required for accurate chromosome segregation.
    EMBO J. 2006 Sep 6;25(17):4033-49 PMID: 16932742
  36. CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis.
    J Cell Biol. 2001 Dec 24;155(7):1147-57 PMID: 11756469
  37. Chromosomal passengers: the four-dimensional regulation of mitotic events.
    Chromosoma. 2004 Nov;113(5):211-22 PMID: 15351889
Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1534-5807
DOI
10.1016/j.devcel.2007.01.003
Email
g.zachos@beatson.gla.ac.uk
Published
2007-02-00
Pages
247-60
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC7115955
Subset
IM
Grants
Wellcome Trust · 043189 · United Kingdom
Wellcome Trust · 073915 · United Kingdom
Corrections
CommentIn
PMID: 17276330
External Links
PubMed source DOI: 10.1016/j.devcel.2007.01.003 PMC Full Text View journal details
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