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Gene Review

BUB1  -  BUB1 mitotic checkpoint serine/threonine...

Homo sapiens

Synonyms: BUB1A, BUB1L, Mitotic checkpoint serine/threonine-protein kinase BUB1, hBUB1
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Disease relevance of BUB1


High impact information on BUB1

  • We show here that a murine homolog of the yeast mitotic checkpoint gene BUB1 localizes to the kinetochore during mitosis [6].
  • Moreover, in some cancers displaying CIN the loss of this checkpoint was associated with the mutational inactivation of a human homologue of the yeast BUB1 gene; BUB1 controls mitotic checkpoints and chromosome segregation in yeast [7].
  • The normal mitotic checkpoints of cells displaying microsatellite instability become defective upon transfer of mutant hBUB1 alleles from either of two CIN cancers [7].
  • Therefore, Bub1-mediated phosphorylation of Cdc20 is required for proper checkpoint signaling [8].
  • We speculate that inhibition of APC/C(Cdc20) by Bub1 in a catalytic fashion may partly account for the exquisite sensitivity of the spindle checkpoint [8].

Chemical compound and disease context of BUB1


Biological context of BUB1


Anatomical context of BUB1

  • Numerical centrosome abnormalities or mutations in genes associated with the mitotic spindle checkpoint (BUB1 and MAD2) are two important mechanisms that can induce abnormal mitosis resulting in aneuploid daughter cells [13].
  • Specifically, when Bub1 is inhibited by RNA interference, or aurora kinase activity is inhibited with the small molecule ZM447439, cells arrest transiently in mitosis following exposure to spindle toxins that prevent microtubule polymerisation [14].
  • Here we show that HeLa cells depleted for Bub1 by RNA interference are defective in checkpoint signaling [8].
  • Using a supervised analysis of the data, the authors found that the best discriminators for molecularly distinguishing between melanoma, benign nevi, and lymph nodes were MLANA, CD63, and BUB1 [15].
  • Spindle checkpoint protein Bub1 corrects mitotic aberrancy induced by human T-cell leukemia virus type I Tax [16].

Associations of BUB1 with chemical compounds

  • This multiprotein complex exhibits a kinase activity with a requirement for lysine 821 in the BUB1 kinase motif, resulting in BUB1 autophosphorylation and phosphorylation of associated MAD1 [17].
  • We show that Plk1 binds to budding uninhibited by benzimidazole 1 (Bub1) in mitotic human cells [18].
  • Consistent with this, we also show that Bub1 is rapidly phosphorylated following brief treatments with nocodazole or taxol [19].
  • A thymine/cytosine polymorphism at 8 bp upstream of the 5' splice acceptor site of exon 10 was observed in Raji cell line and two AML specimens without a resultant change in the expression of hBUB1 [20].

Enzymatic interactions of BUB1

  • Upon checkpoint activation, Bub1 itself is hyperphosphorylated and its kinase activity toward Cdc20 is stimulated [8].
  • We have found that the spindle checkpoint kinase Bub1p becomes phosphorylated by Cdc2p during spindle damage in mitotic cells [21].
  • Bub1 is ubiquitinated by immunopurified APC/C(Cdh1) in vitro [22].

Regulatory relationships of BUB1

  • Furthermore, we show that both Bub1 and aurora kinase activity are required to promote binding of the MCC to the APC/C [14].
  • Our data support the hypothesis that Bub1 compromise triggers p53-dependent senescence, which limits the production of aneuploid and potentially cancerous cells [23].

Other interactions of BUB1

  • These results suggest that inactivation of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 by epigenetic silencing does not seem to play a role in gastric carcinogenesis [24].
  • Human cells contain two related protein kinases, hBUB1 and hBUBR1, that appear to have evolved from a single ancestral BUB1 gene [25].
  • These observations provide a simple explanation of why BubR1 and Mad2 are essential for checkpoint function following spindle destruction, yet Bub1 and aurora B kinase activity are not [14].
  • We suggest therefore that the checkpoint is composed of two arms, one dependent on Bub1, the other on aurora B [14].
  • We examined the contribution of mitotic checkpoint dysfunction and mutations of BUB1 or BUBR1, components of the spindle assembly checkpoint pathway, to chromosomal instability in thyroid cancer [4].

Analytical, diagnostic and therapeutic context of BUB1


  1. Genomic instability at the BUB1 locus in colorectal cancer, but not in non-small cell lung cancer. Jaffrey, R.G., Pritchard, S.C., Clark, C., Murray, G.I., Cassidy, J., Kerr, K.M., Nicolson, M.C., McLeod, H.L. Cancer Res. (2000) [Pubmed]
  2. hBUB1 defects in leukemia and lymphoma cells. Ru, H.Y., Chen, R.L., Lu, W.C., Chen, J.H. Oncogene (2002) [Pubmed]
  3. Genomic instability and colon cancer. Grady, W.M. Cancer Metastasis Rev. (2004) [Pubmed]
  4. Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1. Ouyang, B., Knauf, J.A., Ain, K., Nacev, B., Fagin, J.A. Clin. Endocrinol. (Oxf) (2002) [Pubmed]
  5. Differential expression of the MAD2, BUB1 and HSP27 genes in Barrett's oesophagus-their association with aneuploidy and neoplastic progression. Doak, S.H., Jenkins, G.J., Parry, E.M., Griffiths, A.P., Baxter, J.N., Parry, J.M. Mutat. Res. (2004) [Pubmed]
  6. Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Taylor, S.S., McKeon, F. Cell (1997) [Pubmed]
  7. Mutations of mitotic checkpoint genes in human cancers. Cahill, D.P., Lengauer, C., Yu, J., Riggins, G.J., Willson, J.K., Markowitz, S.D., Kinzler, K.W., Vogelstein, B. Nature (1998) [Pubmed]
  8. Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Tang, Z., Shu, H., Oncel, D., Chen, S., Yu, H. Mol. Cell (2004) [Pubmed]
  9. Somatic mutation of the hBUB1 mitotic checkpoint gene in primary lung cancer. Gemma, A., Seike, M., Seike, Y., Uematsu, K., Hibino, S., Kurimoto, F., Yoshimura, A., Shibuya, M., Harris, C.C., Kudoh, S. Genes Chromosomes Cancer (2000) [Pubmed]
  10. Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts. Musio, A., Montagna, C., Zambroni, D., Indino, E., Barbieri, O., Citti, L., Villa, A., Ried, T., Vezzoni, P. Cancer Res. (2003) [Pubmed]
  11. Human Zwint-1 specifies localization of Zeste White 10 to kinetochores and is essential for mitotic checkpoint signaling. Wang, H., Hu, X., Ding, X., Dou, Z., Yang, Z., Shaw, A.W., Teng, M., Cleveland, D.W., Goldberg, M.L., Niu, L., Yao, X. J. Biol. Chem. (2004) [Pubmed]
  12. The mitotic checkpoint protein hBUB3 and the mRNA export factor hRAE1 interact with GLE2p-binding sequence (GLEBS)-containing proteins. Wang, X., Babu, J.R., Harden, J.M., Jablonski, S.A., Gazi, M.H., Lingle, W.L., de Groen, P.C., Yen, T.J., van Deursen, J.M. J. Biol. Chem. (2001) [Pubmed]
  13. Centrosome amplification and aneuploidy in bone marrow failure patients. Kearns, W.G., Yamaguchi, H., Young, N.S., Liu, J.M. Genes Chromosomes Cancer (2004) [Pubmed]
  14. Bub1 and aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20. Morrow, C.J., Tighe, A., Johnson, V.L., Scott, M.I., Ditchfield, C., Taylor, S.S. J. Cell. Sci. (2005) [Pubmed]
  15. Molecular classification of melanoma using real-time quantitative reverse transcriptase-polymerase chain reaction. Lewis, T.B., Robison, J.E., Bastien, R., Milash, B., Boucher, K., Samlowski, W.E., Leachman, S.A., Dirk Noyes, R., Wittwer, C.T., Perreard, L., Bernard, P.S. Cancer (2005) [Pubmed]
  16. Spindle checkpoint protein Bub1 corrects mitotic aberrancy induced by human T-cell leukemia virus type I Tax. Sasaki, M., Sugimoto, K., Tamayose, K., Ando, M., Tanaka, Y., Oshimi, K. Oncogene (2006) [Pubmed]
  17. Phosphorylation of human MAD1 by the BUB1 kinase in vitro. Seeley, T.W., Wang, L., Zhen, J.Y. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  18. Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1. Qi, W., Tang, Z., Yu, H. Mol. Biol. Cell (2006) [Pubmed]
  19. Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells. Taylor, S.S., Hussein, D., Wang, Y., Elderkin, S., Morrow, C.J. J. Cell. Sci. (2001) [Pubmed]
  20. Expression of hBUB1 in acute myeloid leukemia. Lin, S.F., Lin, P.M., Yang, M.C., Liu, T.C., Chang, J.G., Sue, Y.C., Chen, T.P. Leuk. Lymphoma (2002) [Pubmed]
  21. Function of Cdc2p-dependent Bub1p phosphorylation and Bub1p kinase activity in the mitotic and meiotic spindle checkpoint. Yamaguchi, S., Decottignies, A., Nurse, P. EMBO J. (2003) [Pubmed]
  22. KEN-Box-dependent Degradation of the Bub1 Spindle Checkpoint Kinase by the Anaphase-promoting Complex/Cyclosome. Qi, W., Yu, H. J. Biol. Chem. (2007) [Pubmed]
  23. Surveillance mechanism linking Bub1 loss to the p53 pathway. Gjoerup, O.V., Wu, J., Chandler-Militello, D., Williams, G.L., Zhao, J., Schaffhausen, B., Jat, P.S., Roberts, T.M. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  24. Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer--association with tumour cell proliferation. Grabsch, H., Takeno, S., Parsons, W.J., Pomjanski, N., Boecking, A., Gabbert, H.E., Mueller, W. J. Pathol. (2003) [Pubmed]
  25. The hBUB1 and hBUBR1 kinases sequentially assemble onto kinetochores during prophase with hBUBR1 concentrating at the kinetochore plates in mitosis. Jablonski, S.A., Chan, G.K., Cooke, C.A., Earnshaw, W.C., Yen, T.J. Chromosoma (1998) [Pubmed]
  26. Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines. Myrie, K.A., Percy, M.J., Azim, J.N., Neeley, C.K., Petty, E.M. Cancer Lett. (2000) [Pubmed]
  27. Expression of BUB1 protein in gastric cancer correlates with the histological subtype, but not with DNA ploidy or microsatellite instability. Grabsch, H.I., Askham, J.M., Morrison, E.E., Pomjanski, N., Lickvers, K., Parsons, W.J., Boecking, A., Gabbert, H.E., Mueller, W. J. Pathol. (2004) [Pubmed]
  28. Infrequent mutation of the hBUB1 and hBUBR1 genes in human lung cancer. Sato, M., Sekido, Y., Horio, Y., Takahashi, M., Saito, H., Minna, J.D., Shimokata, K., Hasegawa, Y. Jpn. J. Cancer Res. (2000) [Pubmed]
  29. No mutations of the Bub1 gene in human gastric and oral cancer cell lines. Nakagawa, H., Yokozaki, H., Oue, N., Sugiyama, M., Ishikawa, T., Tahara, E., Yasui, W. Oncol. Rep. (2002) [Pubmed]
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