Abstract
BubR1 is a critical component of the mitotic checkpoint that delays the onset of anaphase until all chromosomes have established bipolar attachment to the microtubules. We previously reported that mutations of the BUB1B gene (encoding BubR1) caused premature chromatid separation (PCS) syndrome, a condition characterized by constitutional aneuploidy and a high risk of childhood cancer. We here report that the cells from PCS syndrome patients have loss of regulation of the centrosome duplication machinery, resulting in centrosome amplification and multipolar mitosis. PCS syndrome cells show increased activity of Polo-like kinase 1 (Plk1), whose knockdown suppresses centrosome amplification. BubR1 localizes to centrosomes, physically interacts with Plk1 and inhibits Plk1 phosphorylation and its kinase activity during interphase. These results unravel a crucial role of BubR1 in preventing centrosome reduplication through negative regulation of Plk1 in interphase cells.
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References
Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A et al. (2004). BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet 36: 744–749.
Balczon R, Bao L, Zimmer WE, Brown K, Zinkowski RP, Brinkley BR . (1995). Dissociation of centrosome replication events from cycles of DNA synthesis and mitotic division in hydroxyurea-arrested Chinese hamster ovary cells. J Cell Biol 130: 105–115.
Barr FA, Sillje HH, Nigg EA . (2004). Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 5: 429–440.
Basto R, Brunk K, Vinadogrova T, Peel N, Franz A, Khodjakov A et al. (2008). Centrosome amplification can initiate tumorigenesis in flies. Cell 133: 1032–1042.
Bornens M, Moudjou M . (1999). Studying the composition and function of centrosomes in vertebrates. Methods Cell Biol 61: 13–34.
Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD et al. (1998). Mutations of mitotic checkpoint genes in human cancers. Nature 392: 300–303.
Carney SA, Tahara H, Swartz CD, Risinger JI, He H, Moore AB et al. (2002). Immortalization of human uterine leiomyoma and myometrial cell lines after induction of telomerase activity: molecular and phenotypic characteristics. Lab Invest 82: 719–728.
Chiba S, Okuda M, Mussman JG, Fukasawa K . (2000). Genomic convergence and suppression of centrosome hyperamplification in primary p53−/− cells in prolonged culture. Exp Cell Res 258: 310–321.
Cleveland DW, Mao Y, Sullivan KF . (2003). Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112: 407–421.
Elowe S, Hummer S, Uldschmid A, Li X, Nigg A . (2007). Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore microtubule interactions. Genes Dev 21: 2205–2219.
Golsteyn RM, Mundt KE, Fry AM, Nigg EA . (1995). Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. J Cell Biol 129: 1617–1628.
Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D et al. (2004). Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 36: 1159–1161.
Jacquemont S, Boceno M, Rival JM, Mechinaud F, David A . (2002). High risk of malignancy in mosaic variegated aneuploidy syndrome. Am J Med Genet 109: 17–21; discussion 16.
Kajii T, Ikeuchi T, Yang ZQ, Nakamura Y, Tsuji Y, Yokomori K et al. (2001). Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: report of five infants. Am J Med Genet 104: 57–64.
Kajii T, Kawai T, Takumi T, Misu H, Mabuchi O, Takahashi Y et al. (1998). Mosaic variegated aneuploidy with multiple congenital abnormalities: homozygosity for total premature chromatid separation trait. Am J Med Genet 78: 245–249.
Kawame H, Sugio Y, Fuyama Y, Hayashi Y, Suzuki H, Kurosawa K et al. (1999). Syndrome of microcephaly, Dandy-Walker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD): report of a new case and review of the literature. J Hum Genet 44: 219–224.
Kops GJ, Weaver BA, Cleveland DW . (2005). On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 5: 773–785.
Lane HA, Nigg EA . (1996). Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol 135: 1701–1713.
Lee KS, Erikson RL . (1997). Plk is a functional homolog of Saccharomyces cerevisiae Cdc5, and elevated Plk activity induces multiple septation structures. Mol Cell Biol 17: 3408–3417.
Liu X, Erikson RL . (2002). Activation of Cdc2/cyclin B and inhibition of centrosome amplification in cells depleted of Plk1 by siRNA. Proc Natl Acad Sci USA 99: 8672–8676.
Loncarek J, Hergert P, Magidson V, Khodjakov A . (2008). Control of daughter centriole formation by the pericentriolar material. Nat Cell Biol 10: 322–328.
Macurek L, Lindqvist A, Lim D, Lampson MA, Lompmaker R, Freire R et al. (2008). Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 455: 119–123.
Matsumura S, Toyoshima F, Nishida E . (2007). Polo-like kinase 1 facilitates chromosome alignment during prometaphase through BubR1. J Biol Chem 282: 15217–15227.
Matsuura S, Ito E, Tauchi H, Komatsu K, Ikeuchi T, Kajii T . (2000). Chromosomal instability syndrome of total premature chromatid separation with mosaic variegated aneuploidy is defective in mitotic-spindle checkpoint. Am J Hum Genet 67: 483–486.
Matsuura S, Matsumoto Y, Morishima K, Izumi H, Matsumoto H, Ito E et al. (2006). Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome. Am J Med Genet A 140: 358–367.
Matsuura S, Weemaes C, Smeets D, Takami H, Kondo N, Sakamoto S et al. (1997). Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen breakage syndrome at chromosome 8q21-24. Am J Hum Genet 60: 1487–1494.
Meraldi P, Honda R, Nigg EA . (2002). Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J 21: 483–492.
Mundt KE, Golsteyn RM, Lane HA, Nigg EA . (1997). On the regulation and function of human polo-like kinase 1 (PLK1): effects of overexpression on cell cycle progression. Biochem Biophys Res Commun 239: 377–385.
Musacchio A, Salmon ED . (2007). The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8: 379–393.
Nigg EA . (2002). Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2: 815–825.
Oikawa T, Okuda M, Ma Z, Goorha R, Tsujimoto H, Inokuma H et al. (2005). Transcriptional control of BubR1 by p53 and suppression of centrosome amplification by BubR1. Mol Cell Biol 25: 4046–4061.
Plaja A, Vendrell T, Smeets D, Sarret E, Gili T, Catala V et al. (2001). Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease. Am J Med Genet 98: 216–223.
Rieder CL, Khodjakov A . (2003). Mitosis through the microscope: advances in seeing inside live dividing cells. Science 300: 91–96.
Seki A, Coppinger JA, Jang CY, Yates JR, Fang G . (2008). Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science 320: 1655–1658.
Toyoshima-Morimoto F, Taniguchi E, Nishida E . (2002). Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep 3: 341–348.
van Vugt MA, Medema RH . (2005). Getting in and out of mitosis with Polo-like kinase-1. Oncogene 24: 2844–2859.
Yu H . (2002). Regulation of APC-Cdc20 by the spindle checkpoint. Curr Opin Cell Biol 14: 706–714.
Acknowledgements
We are grateful to Dr S Tanaka for providing anti-pericentrin antibody and Dr M Ohsugi for providing Flag-Plk1 plasmids. We are also grateful to Dr Y Yamamoto and Dr N Watanabe for technical advice. We thank H Ikeda and H Hatakeyama for technical assistance, and T Jo and A Kamesako for secretarial assistance. We also thank our laboratory members for their continuous encouragement. This work was partly carried out at the Analysis Center of Life Science, Hiroshima University. This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture (to HI and to SM), MEXT priority research projects (to HI and to SM) and the Haraguchi Memorial Cancer Grant Foundation (to HI).
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Izumi, H., Matsumoto, Y., Ikeuchi, T. et al. BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells. Oncogene 28, 2806–2820 (2009). https://doi.org/10.1038/onc.2009.141
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DOI: https://doi.org/10.1038/onc.2009.141
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