title: GSK-3 inhibitors induce chromosome instability.
abstract: BACKGROUND
  Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC) may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 - a protein kinase, which in concert with APC, targets beta-catenin for proteolysis - and ask whether GSK-3 is required for accurate chromosome segregation.
  
  
  RESULTS
  To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain mono-oriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3beta. Cells deficient for GSK-3beta exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3beta repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation.
  
  
  CONCLUSIONS
  Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK-3 inhibitors may induce unwanted side effects by inducing chromosome instability.
authors: Faculty of Life Sciences, Michael Smith Building, Oxford Road, University of Manchester, Manchester M13 9PT, UK. anthony.tighe@manchester.ac.uk
authors: Anthony
authors: A
authors: Tighe
authors: Arpita
authors: A
authors: Ray-Sinha
authors: Oliver D
authors: OD
authors: Staples
authors: Stephen S
authors: SS
authors: Taylor
mesh_terms: D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D034622:RNA Interference; D008941:Spindle Apparatus / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
references: J Cell Sci. 2003 Feb 15;116(Pt 4):637-46
references: 12538764
references: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4365-70
references: 15767571
references: Science. 2005 Mar 25;307(5717):1904-9
references: 15790842
references: J Cell Sci. 2005 Aug 15;118(Pt 16):3639-52
references: 16046481
references: Mol Biol Cell. 2005 Oct;16(10):4609-22
references: 16030254
references: Nat Rev Cancer. 2005 Oct;5(10):773-85
references: 16195750
references: J Cell Sci. 2005 Oct 15;118(Pt 20):4889-900
references: 16219694
references: J Cell Biol. 2005 Oct 24;171(2):197-200
references: 16247021
references: J Cell Sci. 2003 Apr 1;116(Pt 7):1175-86
references: 12615961
references: J Cell Biol. 2003 Apr 28;161(2):267-80
references: 12719470
references: EMBO J. 2003 Jun 2;22(11):2752-63
references: 12773390
references: Science. 2003 Sep 12;301(5639):1547-50
references: 12970569
references: Mol Cell. 2003 Aug;12(2):381-92
references: 14536078
references: J Biol Chem. 2003 Nov 14;278(46):45937-45
references: 12928438
references: Curr Opin Cell Biol. 2003 Dec;15(6):672-83
references: 14644191
references: J Cell Biol. 2003 Dec 8;163(5):949-61
references: 14662741
references: J Biol Chem. 2003 Dec 19;278(51):51786-95
references: 14523000
references: Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6
references: 14698171
references: Genes Dev. 2004 Jan 1;18(1):48-61
references: 14724178
references: Gene. 2005 Nov 21;361:1-12
references: 16185824
references: Trends Cell Biol. 2005 Nov;15(11):589-98
references: 16214339
references: Nature. 2006 Apr 13;440(7086):954-8
references: 16612388
references: EMBO J. 2006 Jun 21;25(12):2814-27
references: 16763565
references: J Cell Sci. 2006 Sep 1;119(Pt 17):3664-75
references: 16912073
references: Science. 2006 Oct 13;314(5797):268-74
references: 16959974
references: J Cell Biol. 2007 Jan 15;176(2):183-95
references: 17227893
references: Trends Cell Biol. 2005 Sep;15(9):486-93
references: 16084093
references: Cell. 2003 Feb 21;112(4):407-21
references: 12600307
references: Diabetes. 2003 Mar;52(3):588-95
references: 12606497
references: J Cell Biol. 2004 Jan 19;164(2):243-53
references: 14734535
references: J Cell Sci. 2004 Mar 1;117(Pt 7):1117-28
references: 14970257
references: J Cell Sci. 2004 Mar 15;117(Pt 8):1577-89
references: 15020684
references: Trends Biochem Sci. 2004 Feb;29(2):95-102
references: 15102436
references: Bioorg Med Chem. 2004 Jun 15;12(12):3167-85
references: 15158785
references: Mol Biol Cell. 2004 Jun;15(6):2978-91
references: 15075372
references: EMBO J. 2004 Jun 2;23(11):2235-45
references: 15152189
references: Nat Rev Drug Discov. 2004 Jun;3(6):479-87
references: 15173837
references: Chromosoma. 2004 Jun;112(8):389-97
references: 15156327
references: Chromosome Res. 2004;12(6):599-616
references: 15289666
references: Annu Rev Cell Dev Biol. 2004;20:337-66
references: 15473844
references: J Cell Sci. 2004 Nov 1;117(Pt 23):5461-77
references: 15509863
references: Eur J Biochem. 1983 Jan 17;130(1):227-34
references: 6402364
references: J Cell Sci. 1992 Nov;103 ( Pt 3):665-75
references: 1478963
references: Mol Cell Biol. 1994 Jan;14(1):831-9
references: 8264650
references: J Cell Biol. 1994 Dec;127(5):1301-10
references: 7962091
references: Nature. 1995 Feb 16;373(6515):630-2
references: 7854422
references: J Cell Biol. 1995 Jun;129(5):1195-204
references: 7775567
references: Cancer Res. 1995 Jul 15;55(14):2972-7
references: 7606712
references: J Cell Biol. 1995 Aug;130(4):941-8
references: 7642709
references: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8455-9
references: 8710892
references: Curr Biol. 1996 Dec 1;6(12):1664-8
references: 8994831
references: Science. 1997 Jan 31;275(5300):632-7
references: 9005842
references: Cell. 1997 May 30;89(5):727-35
references: 9182760
references: J Cell Sci. 1998 Mar;111 ( Pt 5):557-72
references: 9454730
references: J Cell Sci. 2004 Dec 15;117(Pt 26):6339-53
references: 15561772
references: J Cell Biol. 2000 May 15;149(4):761-6
references: 10811817
references: Nature. 2000 Jul 6;406(6791):86-90
references: 10894547
references: Chem Biol. 2000 Oct;7(10):793-803
references: 11033082
references: Mol Med Today. 2000 Dec;6(12):462-9
references: 11099951
references: Curr Biol. 2001 Jan 9;11(1):44-9
references: 11166179
references: Nat Cell Biol. 2001 Apr;3(4):429-32
references: 11283619
references: Nat Cell Biol. 2001 Apr;3(4):433-8
references: 11283620
references: Diabetes. 2001 May;50(5):937-46
references: 11334436
references: EMBO Rep. 2001 Jul;2(7):609-14
references: 11454737
references: Nat Rev Mol Cell Biol. 2001 Oct;2(10):769-76
references: 11584304
references: J Cell Sci. 2001 Dec;114(Pt 24):4385-95
references: 11792804
references: J Med Chem. 2002 Mar 14;45(6):1292-9
references: 11881998
references: Nat Rev Mol Cell Biol. 2002 May;3(5):328-38
references: 11988767
references: Bioorg Med Chem Lett. 2002 Jun 3;12(11):1525-8
references: 12031334
references: Diabetes. 2002 Oct;51(10):2903-10
references: 12351425
references: Nat Rev Mol Cell Biol. 2002 Oct;3(10):731-41
references: 12360190
references: Curr Biol. 2002 Dec 10;12(23):2055-9
references: 12477396