Cullin 1 functions as a centrosomal suppressor of centriole multiplication by regulating polo-like kinase 4 protein levels.
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.
Korzeniewski
Nina
N
University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
Zheng
Leon
L
Cuevas
Rolando
R
Parry
Joshua
J
Chatterjee
Payel
P
Anderton
Brittany
B
Duensing
Anette
A
Münger
Karl
K
Duensing
Stefan
S
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
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
Cell Cycle. 2006 Apr;5(8):853-64
16627997
Mol Cell Biol. 2000 Nov;20(21):8185-97
11027288
J Cell Biol. 1999 May 3;145(3):481-90
10225950
Science. 1993 Dec 24;262(5142):2050-4
8266103
J Cell Biol. 2009 Jan 26;184(2):225-39
19171756
Oncogene. 2006 May 11;25(20):2943-9
16331279
Curr Biol. 2005 Dec 20;15(24):2199-207
16326102
Oncogene. 2007 Sep 20;26(43):6280-8
17438528
Biochim Biophys Acta. 2001;1471(2):M81-8
11342187
Cancer Res. 2001 Mar 15;61(6):2356-60
11289095
J Cell Sci. 2003 Jan 1;116(Pt 1):137-43
12456723
Science. 2008 Nov 7;322(5903):923-9
18988848
Cancer Res. 2008 Dec 15;68(24):10349-57
19074904
Dev Cell. 2007 Aug;13(2):190-202
17681131
Exp Cell Res. 1999 Mar 15;247(2):554-62
10066383
Genes Dev. 1999 Sep 1;13(17):2242-57
10485847
Mol Cell Biol. 2002 Dec;22(23):8375-87
12417738
J Cell Biol. 1971 Jul;50(1):10-34
4998200
Nat Genet. 1999 Oct;23(2):245-8
10508527
J Biol Chem. 2001 Oct 19;276(42):39012-20
11489907
Nat Rev Cancer. 2002 Nov;2(11):815-25
12415252
J Cell Sci. 2007 Jul 1;120(Pt 13):2139-42
17591686
Cell. 2000 Sep 29;103(1):127-40
11051553
Nat Rev Cancer. 2007 Dec;7(12):911-24
18004399
Methods Enzymol. 2005;399:287-309
16338364
Cell. 2001 Jul 13;106(1):95-104
11461705
Adv Exp Med Biol. 2005;570:393-421
18727509
J Biol Chem. 2000 Jan 7;275(1):409-13
10617632
FEBS Lett. 2007 Jan 9;581(1):77-83
17174311
Curr Biol. 2009 Jan 13;19(1):43-9
19084407
Mol Cell Biol. 2008 Oct;28(19):5874-85
18644861
J Cell Biol. 2000 Apr 17;149(2):317-30
10769025
Trends Cell Biol. 2008 Aug;18(8):389-96
18620859
J Cell Biol. 1971 Oct;51(1):286-302
5111878
Biochem Biophys Res Commun. 2005 Jun 10;331(3):694-700
15865924
Curr Biol. 1999 Oct 21;9(20):1191-4
10531039
Dev Cell. 2003 Jun;4(6):799-812
12791266
Dev Cell. 2007 Aug;13(2):203-13
17681132
Mol Biol Cell. 2007 Nov;18(11):4457-69
17804818
Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13738-43
10570142
Environ Mol Mutagen. 2009 Oct;50(8):649-53
19274767
Nat Cell Biol. 2005 Nov;7(11):1140-6
16244668
Dev Cell. 2002 Sep;3(3):339-50
12361598
Cell. 1992 Sep 18;70(6):993-1006
1388095
Cell Biol Int. 2005 May;29(5):375-83
15996491
Nature. 2006 Aug 24;442(7105):947-51
16862117
Mol Biol Cell. 2005 Mar;16(3):1095-107
15616186