title: BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1.
abstract: Bcl-2-interacting mediator of cell death (Bim) is a pro-apoptotic B-cell lymphoma 2 family member implicated in numerous apoptotic stimuli. In particular, Bim is required for cell death mediated by antimitotic agents, however, mitotic regulation of Bim remains poorly understood. Here, we show that the major splice variant of Bim, BimEL, is regulated during mitosis by the Aurora A kinase and protein phosphatase 2A (PP2A). We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL. These findings describe a novel mechanism by which the oncogenic kinase Aurora A promotes cell survival during mitosis by downregulating proapoptotic signals. Notably, we observed that knockdown of Bim significantly increased resistance of cells to the Aurora A inhibitor MLN8054. Inhibitors of Aurora A are currently under investigation as cancer chemotherapeutics and our findings suggest that efficacy of this class of drugs may function in part by enhancing apoptotic activity of BimEL.
authors.affiliation: Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Moustafa-Kamal
authors.forename: I
authors.initials: I
authors.lastname: Gamache
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: J G
authors.initials: JG
authors.lastname: Teodoro
mesh_terms: D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D064096:Aurora Kinase A / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D064096:Aurora Kinase A
references.citation: Nat Cell Biol. 2003 Aug;5(8):733-40
references.pmid: 12844146
references.citation: J Biol Chem. 2003 May 23;278(21):18811-6
references.pmid: 12646560
references.citation: J Neurosci. 2005 Feb 23;25(8):2002-9
references.pmid: 15728840
references.citation: Neuron. 2001 Mar;29(3):615-28
references.pmid: 11301022
references.citation: Cell Cycle. 2011 Nov 15;10(22):3886-96
references.pmid: 22071694
references.citation: Nat Genet. 2004 Jan;36(1):55-62
references.pmid: 14702041
references.citation: Am J Pathol. 2000 Aug;157(2):449-61
references.pmid: 10934149
references.citation: J Biol Chem. 2010 Jul 9;285(28):21849-57
references.pmid: 20444701
references.citation: Nature. 2002 Feb 21;415(6874):922-6
references.pmid: 11859372
references.citation: Cell Signal. 2012 Jan;24(1):170-80
references.pmid: 21924351
references.citation: Cell. 2007 Jun 29;129(7):1337-49
references.pmid: 17604722
references.citation: J Hepatol. 2009 Mar;50(3):518-27
references.pmid: 19155085
references.citation: EMBO J. 2009 Oct 21;28(20):3216-27
references.pmid: 19730412
references.citation: Mol Cell. 2009 Jan 16;33(1):109-16
references.pmid: 19150432
references.citation: Nat Cell Biol. 2010 Sep;12(9):886-93
references.pmid: 20711181
references.citation: Neuron. 2001 Mar;29(3):629-43
references.pmid: 11301023
references.citation: Mol Cell. 2007 Jan 12;25(1):99-112
references.pmid: 17218274
references.citation: Biochem J. 2004 Feb 1;377(Pt 3):597-605
references.pmid: 14561217
references.citation: Science. 1999 Nov 26;286(5445):1735-8
references.pmid: 10576740
references.citation: Cell. 2002 Oct 18;111(2):163-72
references.pmid: 12408861
references.citation: Blood. 2008 Mar 1;111(5):2854-65
references.pmid: 18160664
references.citation: J Cell Biol. 2003 Aug 18;162(4):613-22
references.pmid: 12913110
references.citation: Cell Signal. 2007 Sep;19(9):1964-72
references.pmid: 17624732
references.citation: Methods Enzymol. 2005;399:249-66
references.pmid: 16338361
references.citation: Oncogene. 2003 Oct 2;22(43):6785-93
references.pmid: 14555991
references.citation: Cancer Res. 2007 Dec 15;67(24):11867-75
references.pmid: 18089817
references.citation: EMBO J. 2003 Dec 15;22(24):6653-64
references.pmid: 14657036
references.citation: Cell. 2008 Jul 25;134(2):256-67
references.pmid: 18662541
references.citation: Mol Cell. 2008 May 23;30(4):415-25
references.pmid: 18498746
references.citation: Science. 2008 Jun 20;320(5883):1655-8
references.pmid: 18566290
references.citation: Nature. 2008 Sep 4;455(7209):119-23
references.pmid: 18615013
references.citation: FEBS Lett. 2002 May 22;519(1-3):59-65
references.pmid: 12023018
references.citation: Biochem Pharmacol. 2010 Jan 15;79(2):122-9
references.pmid: 19686703
references.citation: Biochem J. 2005 May 15;388(Pt 1):185-94
references.pmid: 15651977
references.citation: J Cell Sci. 2012 Mar 1;125(Pt 5):1081-7
references.pmid: 22492984
references.citation: Mol Cell. 1999 Mar;3(3):287-96
references.pmid: 10198631
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4419-24
references.pmid: 15070733
references.citation: J Biol Chem. 2003 Dec 19;278(51):51786-95
references.pmid: 14523000
references.citation: J Biol Chem. 2004 May 7;279(19):19643-8
references.pmid: 14990569
references.citation: Mol Cell. 2003 Jun;11(6):1445-56
references.pmid: 12820959
references.citation: Mol Cell. 2007 Apr 27;26(2):301-10
references.pmid: 17466630
references.citation: Oncologist. 2009 Aug;14(8):780-93
references.pmid: 19684075
references.citation: J Biol Chem. 2004 Dec 10;279(50):52175-82
references.pmid: 15469940
references.citation: J Immunol. 2002 May 15;168(10):5024-31
references.pmid: 11994454
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2432-7
references.pmid: 12591950
references.citation: RNA. 2003 Apr;9(4):493-501
references.pmid: 12649500
references.citation: PLoS Med. 2007 Oct;4(10):1681-89; discussion 1690
references.pmid: 17973573
references.citation: Biochim Biophys Acta. 2008 Sep;1786(1):60-72
references.pmid: 18662747
references.citation: Cell Death Differ. 2005 Nov;12 Suppl 2:1473-7
references.pmid: 16247493
references.citation: EMBO Rep. 2002 May;3(5):457-62
references.pmid: 11964384
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9
references.pmid: 15079075
references.citation: Mol Cell Biol. 2010 Dec;30(24):5726-40
references.pmid: 20937773
references.citation: PLoS Med. 2007 Oct;4(10):1669-79; discussion 1680
references.pmid: 17973572
references.citation: Biochem Biophys Res Commun. 2009 Jan 30;379(1):145-50
references.pmid: 19101511
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11
references.pmid: 17360485
references.citation: J Biol Chem. 2004 Mar 5;279(10):8837-47
references.pmid: 14681225
references.citation: PLoS Med. 2007 Oct 9;4(10):e294
references.pmid: 17927446