title: Cullin 1 functions as a centrosomal suppressor of centriole multiplication by regulating polo-like kinase 4 protein levels.
abstract: Abnormal centrosome and centriole numbers are frequently detected in tumor cells where they can contribute to mitotic aberrations that cause chromosome missegregation and aneuploidy. The molecular mechanisms of centriole overduplication in malignant cells, however, are poorly characterized. Here, we show that the core SKP1-cullin-F-box component cullin 1 (CUL1) localizes to maternal centrioles and that CUL1 is critical for suppressing centriole overduplication through multiplication, a recently discovered mechanism whereby multiple daughter centrioles form concurrently at single maternal centrioles. We found that this activity of CUL1 involves the degradation of Polo-like kinase 4 (PLK4) at maternal centrioles. PLK4 is required for centriole duplication and strongly stimulates centriole multiplication when aberrantly expressed. We found that CUL1 is critical for the degradation of active PLK4 following deregulation of cyclin E/cyclin-dependent kinase 2 activity, as is frequently observed in human cancer cells, as well as for baseline PLK4 protein stability. Collectively, our results suggest that CUL1 may function as a tumor suppressor by regulating PLK4 protein levels and thereby restraining excessive daughter centriole formation at maternal centrioles.
authors.affiliation: University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Korzeniewski
authors.forename: Leon
authors.initials: L
authors.lastname: Zheng
authors.forename: Rolando
authors.initials: R
authors.lastname: Cuevas
authors.forename: Joshua
authors.initials: J
authors.lastname: Parry
authors.forename: Payel
authors.initials: P
authors.lastname: Chatterjee
authors.forename: Brittany
authors.initials: B
authors.lastname: Anderton
authors.forename: Anette
authors.initials: A
authors.lastname: Duensing
authors.forename: Karl
authors.initials: K
authors.lastname: Münger
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
mesh_terms: D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002502:Centrioles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism / Q000502:physiology*; D019927:Cyclin E / Q000378:metabolism / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009857:Oncogenes / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D044843:SKP Cullin F-Box Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D019927:Cyclin E; D034741:RNA, Small Interfering; D044843:SKP Cullin F-Box Protein Ligases; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D046988:Proteasome Endopeptidase Complex
references.citation: Cell Cycle. 2006 Apr;5(8):853-64
references.pmid: 16627997
references.citation: Mol Cell Biol. 2000 Nov;20(21):8185-97
references.pmid: 11027288
references.citation: J Cell Biol. 1999 May 3;145(3):481-90
references.pmid: 10225950
references.citation: Science. 1993 Dec 24;262(5142):2050-4
references.pmid: 8266103
references.citation: J Cell Biol. 2009 Jan 26;184(2):225-39
references.pmid: 19171756
references.citation: Oncogene. 2006 May 11;25(20):2943-9
references.pmid: 16331279
references.citation: Curr Biol. 2005 Dec 20;15(24):2199-207
references.pmid: 16326102
references.citation: Oncogene. 2007 Sep 20;26(43):6280-8
references.pmid: 17438528
references.citation: Biochim Biophys Acta. 2001;1471(2):M81-8
references.pmid: 11342187
references.citation: Cancer Res. 2001 Mar 15;61(6):2356-60
references.pmid: 11289095
references.citation: J Cell Sci. 2003 Jan 1;116(Pt 1):137-43
references.pmid: 12456723
references.citation: Science. 2008 Nov 7;322(5903):923-9
references.pmid: 18988848
references.citation: Cancer Res. 2008 Dec 15;68(24):10349-57
references.pmid: 19074904
references.citation: Dev Cell. 2007 Aug;13(2):190-202
references.pmid: 17681131
references.citation: Exp Cell Res. 1999 Mar 15;247(2):554-62
references.pmid: 10066383
references.citation: Genes Dev. 1999 Sep 1;13(17):2242-57
references.pmid: 10485847
references.citation: Mol Cell Biol. 2002 Dec;22(23):8375-87
references.pmid: 12417738
references.citation: J Cell Biol. 1971 Jul;50(1):10-34
references.pmid: 4998200
references.citation: Nat Genet. 1999 Oct;23(2):245-8
references.pmid: 10508527
references.citation: J Biol Chem. 2001 Oct 19;276(42):39012-20
references.pmid: 11489907
references.citation: Nat Rev Cancer. 2002 Nov;2(11):815-25
references.pmid: 12415252
references.citation: J Cell Sci. 2007 Jul 1;120(Pt 13):2139-42
references.pmid: 17591686
references.citation: Cell. 2000 Sep 29;103(1):127-40
references.pmid: 11051553
references.citation: Nat Rev Cancer. 2007 Dec;7(12):911-24
references.pmid: 18004399
references.citation: Methods Enzymol. 2005;399:287-309
references.pmid: 16338364
references.citation: Cell. 2001 Jul 13;106(1):95-104
references.pmid: 11461705
references.citation: Adv Exp Med Biol. 2005;570:393-421
references.pmid: 18727509
references.citation: J Biol Chem. 2000 Jan 7;275(1):409-13
references.pmid: 10617632
references.citation: FEBS Lett. 2007 Jan 9;581(1):77-83
references.pmid: 17174311
references.citation: Curr Biol. 2009 Jan 13;19(1):43-9
references.pmid: 19084407
references.citation: Mol Cell Biol. 2008 Oct;28(19):5874-85
references.pmid: 18644861
references.citation: J Cell Biol. 2000 Apr 17;149(2):317-30
references.pmid: 10769025
references.citation: Trends Cell Biol. 2008 Aug;18(8):389-96
references.pmid: 18620859
references.citation: J Cell Biol. 1971 Oct;51(1):286-302
references.pmid: 5111878
references.citation: Biochem Biophys Res Commun. 2005 Jun 10;331(3):694-700
references.pmid: 15865924
references.citation: Curr Biol. 1999 Oct 21;9(20):1191-4
references.pmid: 10531039
references.citation: Dev Cell. 2003 Jun;4(6):799-812
references.pmid: 12791266
references.citation: Dev Cell. 2007 Aug;13(2):203-13
references.pmid: 17681132
references.citation: Mol Biol Cell. 2007 Nov;18(11):4457-69
references.pmid: 17804818
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13738-43
references.pmid: 10570142
references.citation: Environ Mol Mutagen. 2009 Oct;50(8):649-53
references.pmid: 19274767
references.citation: Nat Cell Biol. 2005 Nov;7(11):1140-6
references.pmid: 16244668
references.citation: Dev Cell. 2002 Sep;3(3):339-50
references.pmid: 12361598
references.citation: Cell. 1992 Sep 18;70(6):993-1006
references.pmid: 1388095
references.citation: Cell Biol Int. 2005 May;29(5):375-83
references.pmid: 15996491
references.citation: Nature. 2006 Aug 24;442(7105):947-51
references.pmid: 16862117
references.citation: Mol Biol Cell. 2005 Mar;16(3):1095-107
references.pmid: 15616186