On the road to cancer: aneuploidy and the mitotic checkpoint (original) (raw)
Flemming, W. Zellsubstanz, kern und zelltheilung. FCW Vogel, Leipzig, (1882). Google Scholar
Boveri, T. Über mehrpolige Mitosen als Mittel zur analyse des zellkerns. Verh. d. phys.med. Ges. Würzburg N. F.35, 67–90 (1902). Google Scholar
von Hansemann, D. Ueber asymmetrische Zellheilteilung in epithelkrebsen und deren biologische bedeutung. Virschows Arch. Pathol. Anat.119, 299–326 (1890). Article Google Scholar
Boveri, T. Zur Frage der Entstehung maligner tumoren. Jena:Gustav Fischer Verlag (1914). Google Scholar
Cancer Cytogenetics (eds Heim, S. & Mitelman, F.) (Wiley Liss Inc., New York, 1995).
Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature386, 623–627 (1997). ArticleCASPubMed Google Scholar
Kops, G. J., Foltz, D. R. & Cleveland, D. W. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc. Natl Acad. Sci. USA101, 8699–8704 (2004). ArticleCASPubMedPubMed Central Google Scholar
Michel, L. et al. Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc. Natl Acad. Sci. USA101, 4459–4464 (2004). References 7 and 8 show that the complete inhibition of the mitotic checkpoint causes death in human tumour cells. ArticleCASPubMedPubMed Central Google Scholar
Duesberg, P. et al. How aneuploidy may cause cancer and genetic instability. Anticancer Res.19, 4887–4906 (1999). CASPubMed Google Scholar
Wang, S. I. et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res.57, 4183–4186 (1997). CASPubMed Google Scholar
Wang, T. L. et al. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc. Natl Acad. Sci. USA101, 3089–3094 (2004). ArticleCASPubMedPubMed Central Google Scholar
Storchova, Z. & Pellman, D. From polyploidy to aneuploidy, genome instability and cancer. Nature Rev. Mol. Cell Biol.5, 45–54 (2004). ArticleCAS Google Scholar
Nigg, E. A. Centrosome aberrations: cause or consequence of cancer progression? Nature Rev. Cancer2, 815–825 (2002). ArticleCAS Google Scholar
Zhou, H. et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nature Genet.20, 189–193 (1998). ArticleCASPubMed Google Scholar
Fukasawa, K., Choi, T., Kuriyama, R., Rulong, S. & Vande Woude, G. F. Abnormal centrosome amplification in the absence of p53. Science271, 1744–1747 (1996). ArticleCASPubMed Google Scholar
Pei, L. & Melmed, S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol. Endocrinol11, 433–441 (1997). ArticleCASPubMed Google Scholar
McGrew, J. T., Goetsch, L., Byers, B. & Baum, P. Requirement for ESP1 in the nuclear division of Saccharomyces cerevisiae. Mol. Biol. Cell3, 1443–1454 (1992). ArticleCASPubMedPubMed Central Google Scholar
Uzawa, S., Samejima, I., Hirano, T., Tanaka, K. & Yanagida, M. The fission yeast cut1+ gene regulates spindle pole body duplication and has homology to the budding yeast ESP1 gene. Cell62, 913–925 (1990). ArticleCASPubMed Google Scholar
Yamamoto, A., Guacci, V. & Koshland, D. Pds1p is required for faithful execution of anaphase in the yeast, Saccharomyces cerevisiae. J. Cell Biol.133, 85–97 (1996). ArticleCASPubMed Google Scholar
Jallepalli, P. V. et al. Securin is required for chromosomal stability in human cells. Cell105, 445–457 (2001). ArticleCASPubMed Google Scholar
Zhang, X. et al. Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol. Endocrinol.13, 156–166 (1999). ArticleCASPubMed Google Scholar
Zhang, X. et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J. Clin. Endocrinol. Metab.84, 761–767 (1999). ArticleCASPubMed Google Scholar
Cimini, D. et al. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J. Cell Biol.153, 517–527 (2001). ArticleCASPubMedPubMed Central Google Scholar
Gassmann, R. et al. Borealin: a novel chromosomal passenger required for stability of the bipolar mitotic spindle. J. Cell Biol.166, 179–191 (2004). ArticleCASPubMedPubMed Central Google Scholar
Kaplan, K. B. et al. A role for the adenomatous polyposis coli protein in chromosome segregation. Nature Cell Biol.3, 429–432 (2001). ArticleCASPubMed Google Scholar
Fodde, R. et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nature Cell Biol.3, 433–438 (2001). ArticleCASPubMed Google Scholar
Fodde, R., Smits, R. & Clevers, H. APC, signal transduction and genetic instability in colorectal cancer. Nature Rev. Cancer1, 55–67 (2001). ArticleCAS Google Scholar
Green, R. A. & Kaplan, K. B. Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus-end attachments caused by a dominant mutation in APC. J. Cell Biol163, 949–961 (2003). ArticleCASPubMedPubMed Central Google Scholar
Shin, H. J. et al. Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability. Cancer Cell4, 483–497 (2003). ArticleCASPubMed Google Scholar
Taylor, S. S. & McKeon, F. Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell89, 727–735 (1997). ArticleCASPubMed Google Scholar
Peters, J. M. The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol. Cell9, 931–943 (2002). ArticleCASPubMed Google Scholar
Cleveland, D. W., Mao, Y. & Sullivan, K. F. Centromeres and kinetochores. From epigenetics to mitotic checkpoint signaling. Cell112, 407–421 (2003). ArticleCASPubMed Google Scholar
Rieder, C. L., Schultz, A., Cole, R. & Sluder, G. Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle. J. Cell Biol.127, 1301–1310 (1994). ArticleCASPubMed Google Scholar
Weiss, E. & Winey, M. The Saccharomyces cerevisiae spindle pole body duplication gene MPS1 is part of a mitotic checkpoint. J. Cell Biol.132, 111–123 (1996). ArticleCASPubMed Google Scholar
Li, R. & Murray, A. W. Feedback control of mitosis in budding yeast. Cell66, 519–531 (1991). ArticleCASPubMed Google Scholar
Hoyt, M. A., Totis, L. & Roberts, B. T. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell66, 507–517 (1991). References 38 and 39 reported the identification of the molecular components of the mitotic checkpoint in budding yeast. ArticleCASPubMed Google Scholar
Abrieu, A. et al. Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell106, 83–93 (2001). ArticleCASPubMed Google Scholar
Jin, D. Y., Spencer, F. & Jeang, K. T. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell93, 81–91 (1998). ArticleCASPubMed Google Scholar
Li, Y. & Benezra, R. Identification of a human mitotic checkpoint gene: hsMAD2. Science274, 246–248 (1996). ArticleCASPubMed Google Scholar
Taylor, S. S., Ha, E. & McKeon, F. The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase. J. Cell Biol.142, 1–11 (1998). ArticleCASPubMedPubMed Central Google Scholar
Abrieu, A., Kahana, J. A., Wood, K. W. & Cleveland, D. W. CENP-E as an essential component of the mitotic checkpoint in vitro. Cell102, 817–826 (2000). ArticleCASPubMed Google Scholar
Chan, G. K., Jablonski, S. A., Sudakin, V., Hittle, J. C. & Yen, T. J. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J. Cell Biol.146, 941–954 (1999). ArticleCASPubMedPubMed Central Google Scholar
Chan, G. K., Jablonski, S. A., Starr, D. A., Goldberg, M. L. & Yen, T. J. Human Zw10 and ROD are mitotic checkpoint proteins that bind to kinetochores. Nature Cell Biol.2, 944–947 (2000). ArticleCASPubMed Google Scholar
Mao, Y., Abrieu, A. & Cleveland, D. W. Activating and silencing the mitotic checkpoint through CENP-E-dependent activation/inactivation of BubR1. Cell114, 87–98 (2003). This study shows how a lack of attachment at the kinetochore can be converted into a catalytic activity that sustains mitotic checkpoint signalling. The microtubule-binding protein CENPE, when unbound by microtubules, directly activates the checkpoint kinase BUBR1, which is an essential mediator of the mitotic checkpoint response. ArticleCASPubMed Google Scholar
Minshull, J., Sun, H., Tonks, N. K. & Murray, A. W. A MAP kinase-dependent spindle assembly checkpoint in Xenopus egg extracts. Cell79, 475–486 (1994). ArticleCASPubMed Google Scholar
Shah, J. V. et al. Dynamics of centromere and kinetochore proteins; implications for checkpoint signaling and silencing. Curr. Biol.14, 942–952 (2004). CASPubMed Google Scholar
Howell, B. J. et al. Spindle checkpoint protein dynamics at kinetochores in living cells. Curr. Biol.14, 953–964 (2004). ArticleCASPubMed Google Scholar
Fang, G., Yu, H. & Kirschner, M. W. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev.12, 1871–1883 (1998). ArticleCASPubMedPubMed Central Google Scholar
Luo, X. et al. The Mad2 spindle checkpoint protein has two distinct natively folded states. Nature Struct. Mol. Biol.11, 338–345 (2004). ArticleCAS Google Scholar
De Antoni, A. et al. The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr. Biol.15, 214–225 (2005). ArticleCASPubMed Google Scholar
Fang, G. Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol. Biol. Cell13, 755–766 (2002). ArticleCASPubMedPubMed Central Google Scholar
Tang, Z., Bharadwaj, R., Li, B. & Yu, H. Mad2-Independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev. Cell1, 227–237 (2001). ArticleCASPubMed Google Scholar
Sudakin, V., Chan, G. K. & Yen, T. J. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J. Cell Biol.154, 925–936 (2001). References 55 and 56 challenged the view that MAD2 alone was the APC/C inhibitor. Although reference 55 showed BUBR1 could directly inhibit the APC/C better than MAD2 could, reference 56 showed that in mitotic HeLa cells, both BUBR1 and MAD2, together with BUB3, were found in complex with CDC20, and that this complex was a very potent inhibitor of the APC/C. ArticleCASPubMedPubMed Central Google Scholar
Hwang, L. H. et al. Budding yeast Cdc20: a target of the spindle checkpoint. Science279, 1041–1044 (1998). ArticleCASPubMed Google Scholar
Kallio, M., Weinstein, J., Daum, J. R., Burke, D. J. & Gorbsky, G. J. Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events. J. Cell Biol.141, 1393–1406 (1998). ArticleCASPubMedPubMed Central Google Scholar
Chen, R. H. Phosphorylation and activation of Bub1 on unattached chromosomes facilitate the spindle checkpoint. EMBO J.23, 3113–3121 (2004). ArticleCASPubMedPubMed Central Google Scholar
Ditchfield, C. et al. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J. Cell Biol.161, 267–280 (2003). ArticleCASPubMedPubMed Central Google Scholar
Camasses, A., Bogdanova, A., Shevchenko, A. & Zachariae, W. The CCT chaperonin promotes activation of the anaphase-promoting complex through the generation of functional Cdc20. Mol. Cell12, 87–100 (2003). ArticleCASPubMed Google Scholar
Lens, S. M. et al. Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J.22, 2934–2947 (2003). ArticleCASPubMedPubMed Central Google Scholar
Hauf, S. et al. The small molecule hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J. Cell Biol.161, 281–294 (2003). ArticleCASPubMedPubMed Central Google Scholar
Tanaka, T. U. et al. Evidence that the Ipl1–Sli15 (aurora kinase–INCENP) complex promotes chromosome bi-orientation by altering kinetochore–spindle pole connections. Cell108, 317–329 (2002). ArticleCASPubMed Google Scholar
Lampson, M. A. & Kapoor, T. M. The human mitotic checkpoint protein BubR1 regulates chromosome–spindle attachments. Nature Cell Biol.7, 93–98 (2005). ArticleCASPubMed Google Scholar
Putkey, F. R. et al. Unstable kinetochore-microtubule capture and chromosomal instability following deletion of CENP-E. Dev. Cell3, 351–365 (2002). ArticleCASPubMed Google Scholar
Weaver, B. A. et al. Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss. J. Cell Biol.162, 551–563 (2003). ArticleCASPubMedPubMed Central Google Scholar
Habu, T., Kim, S. H., Weinstein, J. & Matsumoto, T. Identification of a MAD2-binding protein, CMT2, and its role in mitosis. EMBO J.21, 6419–6428 (2002). ArticleCASPubMedPubMed Central Google Scholar
Xia, G. et al. Conformation-specific binding of p31(comet) antagonizes the function of Mad2 in the spindle checkpoint. EMBO J.23, 3133–3143 (2004). ArticleCASPubMedPubMed Central Google Scholar
Kienitz, A., Vogel, C., Morales, I., Muller, R. & Bastians, H. Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol. Oncogene24, 4301–4310 (2005). ArticleCASPubMed Google Scholar
Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature392, 300–303 (1998). First study to identify mutant alleles of the mitotic checkpoint proteins BUB1 and BUBR1 in human colorectal cancer cell lines. ArticleCASPubMed Google Scholar
Dai, W. et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res.64, 440–445 (2004). ArticleCASPubMed Google Scholar
Babu, J. R. et al. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J. Cell Biol.160, 341–353 (2003). ArticleCASPubMedPubMed Central Google Scholar
Michel, M. L. et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature409, 355–359 (2001). References 74 and 75 provided proof-of-principle that reduced levels of a mitotic checkpoint protein can cause checkpoint malfunction and CIN, and thereby contribute to tumour formation. ArticleCASPubMed Google Scholar
Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature Genet.36, 744–749 (2004). ArticleCASPubMed Google Scholar
Musio, A. et al. Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts. Cancer Res.63, 2855–2863 (2003). CASPubMed Google Scholar
Wang, Q. et al. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood103, 1278–1285 (2004). ArticleCASPubMed Google Scholar
Myung, K., Smith, S. & Kolodner, R. D. Mitotic checkpoint function in the formation of gross chromosomal rearrangements in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA101, 15980–15985 (2004). ArticleCASPubMedPubMed Central Google Scholar
Iouk, T., Kerscher, O., Scott, R. J., Basrai, M. A. & Wozniak, R. W. The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint. J. Cell Biol.159, 807–819 (2002). ArticleCASPubMedPubMed Central Google Scholar
Campbell, M. S., Chan, G. K. & Yen, T. J. Mitotic checkpoint proteins HsMAD1 and HsMAD2 are associated with nuclear pore complexes in interphase. J. Cell. Sci.114, 953–963 (2001). CASPubMed Google Scholar
Rao, C. V. et al. Colonic tumorigenesis in BubR1+/− _Apc_Min/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc. Natl Acad. Sci. USA102, 4365–4370 (2005). ArticleCASPubMedPubMed Central Google Scholar
Connor, F. et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nature Genet.17, 423–430 (1997). ArticleCASPubMed Google Scholar
Friedman, L. S. et al. Thymic lymphomas in mice with a truncating mutation in Brca2. Cancer Res.58, 1338–1343 (1998). CASPubMed Google Scholar
Lee, H. et al. Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2. Mol. Cell4, 1–10 (1999). ArticleCASPubMed Google Scholar
Rieder, C. L. & Maiato, H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev. Cell7, 637–651 (2004). ArticleCASPubMed Google Scholar
Ouyang, B., Knauf, J. A., Ain, K., Nacev, B. & Fagin, J. A. Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1. Clin. Endocrinol. (Oxf.)56, 341–350 (2002). ArticleCAS Google Scholar
Takahashi, T. et al. Identification of frequent impairment of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes, hsMAD2 and p55CDC, in human lung cancers. Oncogene18, 4295–4300 (1999). ArticleCASPubMed Google Scholar
Wang, X. et al. Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Cancer Res.62, 1662–1668 (2002). CASPubMed Google Scholar
Tighe, A., Johnson, V. L., Albertella, M. & Taylor, S. S. Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep.2, 609–614 (2001). ArticleCASPubMedPubMed Central Google Scholar
Saeki, A. et al. Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer94, 2047–2054 (2002). ArticleCASPubMed Google Scholar
Yoon, D. S. et al. Variable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer. Am. J. Pathol.161, 391–397 (2002). ArticlePubMedPubMed Central Google Scholar
Grigorova, M., Staines, J. M., Ozdag, H., Caldas, C. & Edwards, P. A. Possible causes of chromosome instability: comparison of chromosomal abnormalities in cancer cell lines with mutations in BRCA1, BRCA2, CHK2 and BUB1. Cytogenet. Genome Res.104, 333–340 (2004). ArticleCASPubMed Google Scholar
Gemma, A. et al. Somatic mutation of the hBUB1 mitotic checkpoint gene in primary lung cancer. Genes Chromosomes Cancer29, 213–218 (2000). ArticleCASPubMed Google Scholar
Hempen, P. M., Kurpad, H., Calhoun, E. S., Abraham, S. & Kern, S. E. A double missense variation of the BUB1 gene and a defective mitotic spindle checkpoint in the pancreatic cancer cell line Hs766T. Hum. Mutat.21, 445 (2003). ArticlePubMedCAS Google Scholar
Hernando, E. et al. Molecular analyses of the mitotic checkpoint components hsMAD2, hBUB1 and hBUB3 in human cancer. Int. J. Cancer95, 223–227 (2001). ArticleCASPubMed Google Scholar
Imai, Y., Shiratori, Y., Kato, N., Inoue, T. & Omata, M. Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers. Jpn. J. Cancer Res.90, 837–840 (1999). ArticleCASPubMedPubMed Central Google Scholar
Ohshima, K. et al. Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma. Cancer Lett.158, 141–150 (2000). ArticleCASPubMed Google Scholar
Nomoto, S. et al. Search for in vivo somatic mutations in the mitotic checkpoint gene, hMAD1, in human lung cancers. Oncogene18, 7180–7183 (1999). ArticleCASPubMed Google Scholar
Percy, M. J. et al. Expression and mutational analyses of the human MAD2L1 gene in breast cancer cells. Genes Chromosomes Cancer29, 356–362 (2000). ArticleCASPubMed Google Scholar
Tsukasaki, K. et al. Mutations in the mitotic check point gene, MAD1L1, in human cancers. Oncogene20, 3301–3305 (2001). ArticleCASPubMed Google Scholar
Shichiri, M., Yoshinaga, K., Hisatomi, H., Sugihara, K. & Hirata, Y. Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival. Cancer Res.62, 13–17 (2002). CASPubMed Google Scholar
Wang, Z. et al. Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res.64, 2998–3001 (2004). ArticleCASPubMed Google Scholar
Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet.36, 1159–1161 (2004). ArticleCASPubMed Google Scholar
Haruki, N. et al. Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers. Cancer Lett.162, 201–205 (2001). ArticleCASPubMed Google Scholar
Olesen, S. H., Thykjaer, T. & Orntoft, T. F. Mitotic checkpoint genes hBUB1, hBUB1B, hBUB3 and TTK in human bladder cancer, screening for mutations and loss of heterozygosity. Carcinogenesis22, 813–815 (2001). ArticleCASPubMed Google Scholar
Cahill, D. P. et al. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics58, 181–187 (1999). ArticleCASPubMed Google Scholar
Myrie, K. A., Percy, M. J., Azim, J. N., Neeley, C. K. & Petty, E. M. Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines. Cancer Lett.152, 193–199 (2000). ArticleCASPubMed Google Scholar
Scolnick, D. M. & Halazonetis, T. D. Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Nature406, 430–435 (2000). ArticleCASPubMed Google Scholar
Tao, W. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nature Genet.21, 177–181 (1999). ArticleCASPubMed Google Scholar
Song, M. S. et al. The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC–Cdc20 complex. Nature Cell Biol.6, 129–137 (2004). ArticleCASPubMed Google Scholar
Grabsch, H. et al. Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer — association with tumour cell proliferation. J. Pathol.200, 16–22 (2003). ArticleCASPubMed Google Scholar
Hernando, E. et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature430, 797–802 (2004). This study shows how a tumour suppressor can manipulate the mitotic checkpoint to create CIN. Aneuploidy occurs in RB-negative tumor cells via increased levels of MAD2.MAD2L1is a target gene of the RB-controlled transcription factor E2F. ArticleCASPubMed Google Scholar
Cheung, H. W. et al. Mitotic arrest deficient 2 expression induces chemosensitization to a DNA-damaging agent, cisplatin, in nasopharyngeal carcinoma cells. Cancer Res.65, 1450–1458 (2005). ArticleCASPubMed Google Scholar
Wang, R. H., Yu, H. & Deng, C. X. A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle heckpoint. Proc. Natl Acad. Sci. USA101, 17108–17113 (2004). ArticleCASPubMedPubMed Central Google Scholar
van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature415, 530–536 (2002). ArticleCAS Google Scholar
Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev.16, 245–256 (2002). ArticleCASPubMedPubMed Central Google Scholar
Chun, A. C. & Jin, D. Y. Transcriptional regulation of mitotic checkpoint gene MAD1 by p53. J. Biol. Chem.278, 37439–37450 (2003). ArticleCASPubMed Google Scholar
Iwanaga, Y. & Jeang, K. T. Expression of mitotic spindle checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 mutant. Cancer Res.62, 2618–2624 (2002). CASPubMed Google Scholar
Gupta, A., Inaba, S., Wong, O. K., Fang, G. & Liu, J. Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1. Oncogene22, 7593–7599 (2003). ArticleCASPubMed Google Scholar
Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nature Rev. Cancer4, 253–265 (2004). ArticleCAS Google Scholar
Keen, N. & Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nature Rev. Cancer4, 927–936 (2004). ArticleCAS Google Scholar
Harrington, E. A. et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nature Med.10, 262–267 (2004). ArticleCASPubMed Google Scholar
Dorer, R. K. et al. A small-molecule inhibitor of Mps1 blocks the spindle-checkpoint response to a lack of tension on mitotic chromosomes. Curr. Biol.15, 1070–1076 (2005). ArticleCASPubMed Google Scholar
Larsen, N. A. & Harrison, S. C. Crystal structure of the spindle assembly checkpoint protein Bub3. J. Mol. Biol.344, 885–892 (2004). ArticleCASPubMed Google Scholar
Luo, X. et al. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nature Struct. Biol.7, 224–229 (2000). ArticleCASPubMed Google Scholar
Tang, Z., Shu, H., Oncel, D., Chen, S. & Yu, H. Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Mol. Cell16, 387–397 (2004). ArticleCASPubMed Google Scholar
Chen, R. H., Shevchenko, A., Mann, M. & Murray, A. W. Spindle checkpoint protein Xmad1 recruits Xmad2 to unattached kinetochores. J. Cell Biol.143, 283–295 (1998). ArticleCASPubMedPubMed Central Google Scholar