This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dai, W. Articles by Rao, C. V. Search for Related Content PubMed PubMed Citation Articles by Dai, W. Articles by Rao, C. V.

Slippage of Mitotic Arrest and Enhanced Tumor Development in Mice with BubR1 Haploinsufficiency

¹ Division of Molecular Carcinogenesis, Department of Medicine, New York Medical College, Valhalla, New York;
² Core Facility for Histopathology, Albert Einstein College of Medicine, Bronx, New York;
³ Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and
⁴ Institute for Cancer Prevention, Valhalla, New York

A compromised spindle checkpoint is thought to play a key role in genetic instability that predisposes cells to malignant transformation. Loss of function mutations of BubR1, an important component of the spindle checkpoint, have been detected in human cancers. Here we show that BubR1^+/- mouse embryonic fibroblasts are defective in spindle checkpoint activation, contain a significantly reduced amount of securin and Cdc20, and exhibit a greater level of micronuclei than do wild-type cells. RNA interference-mediated down-regulation of BubR1 also greatly reduced securin level. Moreover, compared with wild-type littermates, BubR1^+/- mice rapidly develop lung as well as intestinal adenocarcinomas in response to challenge with carcinogen. BubR1 is thus essential for spindle checkpoint activation and tumor suppression.

This article has been cited by other articles:

				J. H. van Ree, K. B. Jeganathan, L. Malureanu, and J. M. van Deursen Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation J. Cell Biol., January 11, 2010; 188(1): 83 - 100. [Abstract] [Full Text] [PDF]

				X.-s. Liu, X.-d. Zhao, X. Wang, Y.-x. Yao, L.-l. Zhang, R.-z. Shu, W.-h. Ren, Y. Huang, L. Huang, M.-m. Gu, et al. Germinal Cell Aplasia in Kif18a Mutant Male Mice Due to Impaired Chromosome Congression and Dysregulated BubR1 and CENP-E Genes & Cancer, January 1, 2010; 1(1): 26 - 39. [Abstract] [Full Text] [PDF]

				M. Li, X. Fang, Z. Wei, J. P. York, and P. Zhang Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice J. Cell Biol., June 15, 2009; 185(6): 983 - 994. [Abstract] [Full Text] [PDF]

				I. Ganmore, G. Smooha, and S. Izraeli Constitutional aneuploidy and cancer predisposition Hum. Mol. Genet., April 15, 2009; 18(R1): R84 - R93. [Abstract] [Full Text] [PDF]

				R. Tomasini, K. Tsuchihara, C. Tsuda, S. K. Lau, M. Wilhelm, A. Ruffini, M.-s. Tsao, J. L. Iovanna, A. Jurisicova, G. Melino, et al. TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity PNAS, January 20, 2009; 106(3): 797 - 802. [Abstract] [Full Text] [PDF]

				H.-S. Kim, Y.-K. Jeon, G.-H. Ha, H.-Y. Park, Y.-J. Kim, H.-J. Shin, C. G. Lee, D.-H. Chung, and C.-W. Lee Functional Interaction between BubR1 and Securin in an Anaphase-Promoting Complex/CyclosomeCdc20-Independent Manner Cancer Res., January 1, 2009; 69(1): 27 - 36. [Abstract] [Full Text] [PDF]

				M. Schliekelman, D. O. Cowley, R. O'Quinn, T. G. Oliver, L. Lu, E.D. Salmon, and T. Van Dyke Impaired Bub1 Function In vivo Compromises Tension-Dependent Checkpoint Function Leading to Aneuploidy and Tumorigenesis Cancer Res., January 1, 2009; 69(1): 45 - 54. [Abstract] [Full Text] [PDF]

				E. Diaz-Rodriguez, R. Sotillo, J.-M. Schvartzman, and R. Benezra Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation in vivo PNAS, October 28, 2008; 105(43): 16719 - 16724. [Abstract] [Full Text] [PDF]

				D. Qiao, X. Yang, K. Meyer, and A. Friedl Glypican-1 Regulates Anaphase Promoting Complex/Cyclosome Substrates and Cell Cycle Progression in Endothelial Cells Mol. Biol. Cell, July 1, 2008; 19(7): 2789 - 2801. [Abstract] [Full Text] [PDF]

				Y. Suehiro, T. Okada, T. Okada, K. Anno, N. Okayama, K. Ueno, M. Hiura, M. Nakamura, T. Kondo, A. Oga, et al. Aneuploidy Predicts Outcome in Patients with Endometrial Carcinoma and Is Related to Lack of CDH13 Hypermethylation Clin. Cancer Res., June 1, 2008; 14(11): 3354 - 3361. [Abstract] [Full Text] [PDF]

				M. Kim, J. Liao, M. L. Dowling, K. R. Voong, S. E. Parker, S. Wang, W. S. El-Deiry, and G. D. Kao TRAIL Inactivates the Mitotic Checkpoint and Potentiates Death Induced by Microtubule-Targeting Agents in Human Cancer Cells Cancer Res., May 1, 2008; 68(9): 3440 - 3449. [Abstract] [Full Text] [PDF]

				H. Ebi, K. Matsuo, N. Sugito, M. Suzuki, H. Osada, K. Tajima, R. Ueda, and T. Takahashi Novel NBS1 Heterozygous Germ Line Mutation Causing MRE11-Binding Domain Loss Predisposes to Common Types of Cancer Cancer Res., December 1, 2007; 67(23): 11158 - 11165. [Abstract] [Full Text] [PDF]

				G.-H. Ha, K.-H. Baek, H.-S. Kim, S.-J. Jeong, C.-M. Kim, F. McKeon, and C.-W. Lee p53 Activation in Response to Mitotic Spindle Damage Requires Signaling via BubR1-Mediated Phosphorylation Cancer Res., August 1, 2007; 67(15): 7155 - 7164. [Abstract] [Full Text] [PDF]

				Y. Niikura, A. Dixit, R. Scott, G. Perkins, and K. Kitagawa BUB1 mediation of caspase-independent mitotic death determines cell fate J. Cell Biol., July 10, 2007; 178(2): 283 - 296. [Abstract] [Full Text] [PDF]

				L. Magnaghi-Jaulin, G. Eot-Houllier, G. Fulcrand, and C. Jaulin Histone Deacetylase Inhibitors Induce Premature Sister Chromatid Separation and Override the Mitotic Spindle Assembly Checkpoint Cancer Res., July 1, 2007; 67(13): 6360 - 6367. [Abstract] [Full Text] [PDF]

				E. Myslinski, M.-A. Gerard, A. Krol, and P. Carbon Transcription of the human cell cycle regulated BUB1B gene requires hStaf/ZNF143 Nucleic Acids Res., May 11, 2007; 35(10): 3453 - 3464. [Abstract] [Full Text] [PDF]

				I. Perez de Castro, G. de Carcer, and M. Malumbres A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy Carcinogenesis, May 1, 2007; 28(5): 899 - 912. [Abstract] [Full Text] [PDF]

				A. Boyapati, M. Yan, L. F. Peterson, J. R. Biggs, M. M. Le Beau, and D.-E. Zhang A leukemia fusion protein attenuates the spindle checkpoint and promotes aneuploidy Blood, May 1, 2007; 109(9): 3963 - 3971. [Abstract] [Full Text] [PDF]

				L. Groth-Pedersen, M. S. Ostenfeld, M. Hoyer-Hansen, J. Nylandsted, and M. Jaattela Vincristine Induces Dramatic Lysosomal Changes and Sensitizes Cancer Cells to Lysosome-Destabilizing Siramesine Cancer Res., March 1, 2007; 67(5): 2217 - 2225. [Abstract] [Full Text] [PDF]

				V. Trachana, K. H. M. van Wely, A. A. Guerrero, A. Futterer, and C. Martinez-A Dido disruption leads to centrosome amplification and mitotic checkpoint defects compromising chromosome stability PNAS, February 20, 2007; 104(8): 2691 - 2696. [Abstract] [Full Text] [PDF]

				Y. Iwanaga, Y.-H. Chi, A. Miyazato, S. Sheleg, K. Haller, J.-M. Peloponese Jr., Y. Li, J. M. Ward, R. Benezra, and K.-T. Jeang Heterozygous Deletion of Mitotic Arrest-Deficient Protein 1 (MAD1) Increases the Incidence of Tumors in Mice Cancer Res., January 1, 2007; 67(1): 160 - 166. [Abstract] [Full Text] [PDF]

				H. Y. Yamada and G. J. Gorbsky Spindle checkpoint function and cellular sensitivity to antimitotic drugs Mol. Cancer Ther., December 1, 2006; 5(12): 2963 - 2969. [Full Text] [PDF]

				G. M. Chin and R. Herbst Induction of apoptosis by monastrol, an inhibitor of the mitotic kinesin Eg5, is independent of the spindle checkpoint. Mol. Cancer Ther., October 1, 2006; 5(10): 2580 - 2591. [Abstract] [Full Text] [PDF]

				N. Chester, H. Babbe, J. Pinkas, C. Manning, and P. Leder Mutation of the Murine Bloom's Syndrome Gene Produces Global Genome Destabilization Mol. Cell. Biol., September 1, 2006; 26(17): 6713 - 6726. [Abstract] [Full Text] [PDF]

				W. Dai and X. Wang Aging in check. Sci. Aging Knowl. Environ., March 15, 2006; 2006(7): pe9 - pe9. [Abstract] [Full Text]

				D. J. Baker, K. B. Jeganathan, L. Malureanu, C. Perez-Terzic, A. Terzic, and J. M.A. van Deursen Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J. Cell Biol., February 13, 2006; 172(4): 529 - 540. [Abstract] [Full Text] [PDF]

				B. Yuan, Y. Xu, J.-H. Woo, Y. Wang, Y. K. Bae, D.-S. Yoon, R. P. Wersto, E. Tully, K. Wilsbach, and E. Gabrielson Increased Expression of Mitotic Checkpoint Genes in Breast Cancer Cells with Chromosomal Instability Clin. Cancer Res., January 15, 2006; 12(2): 405 - 410. [Abstract] [Full Text] [PDF]

				M. Kim, K. Murphy, F. Liu, S. E. Parker, M. L. Dowling, W. Baff, and G. D. Kao Caspase-Mediated Specific Cleavage of BubR1 Is a Determinant of Mitotic Progression Mol. Cell. Biol., November 1, 2005; 25(21): 9232 - 9248. [Abstract] [Full Text] [PDF]

				D. O. Cowley, G. W. Muse, and T. Van Dyke A Dominant Interfering Bub1 Mutant Is Insufficient To Induce or Alter Thymic Tumorigenesis In Vivo, Even in a Sensitized Genetic Background Mol. Cell. Biol., September 1, 2005; 25(17): 7796 - 7802. [Abstract] [Full Text] [PDF]

				T. Oikawa, M. Okuda, Z. Ma, R. Goorha, H. Tsujimoto, H. Inokuma, and K. Fukasawa Transcriptional Control of BubR1 by p53 and Suppression of Centrosome Amplification by BubR1 Mol. Cell. Biol., May 15, 2005; 25(10): 4046 - 4061. [Abstract] [Full Text] [PDF]

				L. B. Smilenov, H. B. Lieberman, S. A. Mitchell, R. A. Baker, K. M. Hopkins, and E. J. Hall Combined Haploinsufficiency for ATM and RAD9 as a Factor in Cell Transformation, Apoptosis, and DNA Lesion Repair Dynamics Cancer Res., February 1, 2005; 65(3): 933 - 938. [Abstract] [Full Text] [PDF]

				F. Sun, I. Betzendahl, F. Pacchierotti, R. Ranaldi, J. Smitz, R. Cortvrindt, and U. Eichenlaub-Ritter Aneuploidy in mouse metaphase II oocytes exposed in vivo and in vitro in preantral follicle culture to nocodazole Mutagenesis, January 1, 2005; 20(1): 65 - 75. [Abstract] [Full Text] [PDF]

				H. Wang, X. Hu, X. Ding, Z. Dou, Z. Yang, A. W. Shaw, M. Teng, D. W. Cleveland, M. L. Goldberg, L. Niu, et al. Human Zwint-1 Specifies Localization of Zeste White 10 to Kinetochores and Is Essential for Mitotic Checkpoint Signaling J. Biol. Chem., December 24, 2004; 279(52): 54590 - 54598. [Abstract] [Full Text] [PDF]

				K. Myung, S. Smith, and R. D. Kolodner Mitotic checkpoint function in the formation of gross chromosomal rearrangements in Saccharomyces cerevisiae PNAS, November 9, 2004; 101(45): 15980 - 15985. [Abstract] [Full Text] [PDF]

				G. J. P. L. Kops, D. R. Foltz, and D. W. Cleveland Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint PNAS, June 8, 2004; 101(23): 8699 - 8704. [Abstract] [Full Text] [PDF]