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Gene Review

MAD2L1  -  MAD2 mitotic arrest deficient-like 1 (yeast)

Homo sapiens

Synonyms: HSMAD2, HsMAD2, MAD2, MAD2-like protein 1, Mitotic arrest deficient 2-like protein 1, ...
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Disease relevance of MAD2L1


High impact information on MAD2L1

  • Depletion of PICH causes the selective loss of Mad2 from kinetochores and completely abrogates the spindle checkpoint, resulting in massive chromosome missegregation [6].
  • In addition, in vitro cdk1-phosphorylated Cdc20 interacts with Mad2 rather than APC/ C [7].
  • When injected into Xenopus embryos, hMAD2 arrests cells at mitosis with an inactive APC [8].
  • The template model proposes that Mad1-Mad2 at kinetochores acts as a template to change the conformation of another binding molecule of Mad2 [9].
  • Arrest with ICRF-193 is not accompanied by recruitment of Mad2 or Bub1 to kinetochores, nor by phosphorylation of the histone H2AX, indicating arrest by ICRF-193 is not due to activation of the spindle assembly checkpoint, nor is it a response to DNA damage [10].

Chemical compound and disease context of MAD2L1


Biological context of MAD2L1


Anatomical context of MAD2L1


Associations of MAD2L1 with chemical compounds

  • In addition, the association of Mad2 with the APC/C(cdc20) complex and the accumulation of Pds1, an anaphase inhibitor, were remarkably reduced in arsenite-arrested mitotic cells as compared with nocodazole-arrested mitotic cells [19].
  • To additionally understand the significance of the MAD2 to mitotic checkpoint control, we established an inducible expression system in which MAD2 was induced by the addition of ponasterone A [5].
  • Further, we have identified a unique polyhistidine motif with metal binding property adjacent to this second binding domain that may be important for maintaining the overall conformation of Cdc20 for its binding to Mad2 [20].
  • Previously, we first reported that a key regulator of the mitotic checkpoint, mitotic arrest deficient-2 (MAD2), was a mediator of cisplatin sensitivity in human cancer cells [21].

Physical interactions of MAD2L1

  • The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20 [14].
  • Mad2 is a component of the SAC effector complex that sequesters Cdc20 to halt anaphase [22].
  • More interestingly, REV7 interacts with hMAD2 and therefore might function in the cell cycle control by affecting the activation of APC (anaphase promoting complex) [23].
  • The structure of the O-Mad2-C-Mad2 conformational dimer is consistent with a catalytic model in which a C-Mad2 template facilitates the binding of O-Mad2 to Cdc20, the target of Mad2 in the spindle checkpoint [24].
  • Depletion of Tpr in HeLa cells disrupts the NPC localization of Mad1 and Mad2 during interphase and decreases the levels of Mad1-bound Mad2 [25].

Regulatory relationships of MAD2L1

  • The mitotic arrest deficiency 2 (Mad2) spindle checkpoint protein inhibits APC/C through binding to its mitotic-specific activator, Cdc20 [26].

Other interactions of MAD2L1

  • Mad1 and Cdc20 contain Mad2 binding motifs that share a common consensus [14].
  • Binding of one of these ligands, MBP1, triggers an extensive rearrangement of the tertiary structure of Mad2 [14].
  • In addition, we have identified an interaction between hREV7 and hMAD2 but not hMAD1 [27].
  • 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 [28].
  • Analysis of BubR1 complexes suggests that both of these arms converge on the mitotic checkpoint complex (MCC), which includes BubR1, Bub3, Mad2 and Cdc20 [28].

Analytical, diagnostic and therapeutic context of MAD2L1


  1. Frequent mutations of human Mad2, but not Bub1, in gastric cancers cause defective mitotic spindle checkpoint. Kim, H.S., Park, K.H., Kim, S.A., Wen, J., Park, S.W., Park, B., Gham, C.W., Hyung, W.J., Noh, S.H., Kim, H.K., Song, S.Y. Mutat. Res. (2005) [Pubmed]
  2. 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]
  3. Prediction of lymph node metastasis in patients with endometrioid endometrial cancer using expression microarray. Bidus, M.A., Risinger, J.I., Chandramouli, G.V., Dainty, L.A., Litzi, T.J., Berchuck, A., Barrett, J.C., Maxwell, G.L. Clin. Cancer Res. (2006) [Pubmed]
  4. Expression and mutational analyses of the human MAD2L1 gene in breast cancer cells. Percy, M.J., Myrie, K.A., Neeley, C.K., Azim, J.N., Ethier, S.P., Petty, E.M. Genes Chromosomes Cancer (2000) [Pubmed]
  5. Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Wang, X., Jin, D.Y., Ng, R.W., Feng, H., Wong, Y.C., Cheung, A.L., Tsao, S.W. Cancer Res. (2002) [Pubmed]
  6. PICH, a Centromere-Associated SNF2 Family ATPase, Is Regulated by Plk1 and Required for the Spindle Checkpoint. Baumann, C., K??rner, R., Hofmann, K., Nigg, E.A. Cell (2007) [Pubmed]
  7. The spindle checkpoint requires cyclin-dependent kinase activity. D'Angiolella, V., Mari, C., Nocera, D., Rametti, L., Grieco, D. Genes Dev. (2003) [Pubmed]
  8. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Fang, G., Yu, H., Kirschner, M.W. Genes Dev. (1998) [Pubmed]
  9. Kinetochore structure and function. Chan, G.K., Liu, S.T., Yen, T.J. Trends Cell Biol. (2005) [Pubmed]
  10. Inhibition of DNA decatenation, but not DNA damage, arrests cells at metaphase. Skoufias, D.A., Lacroix, F.B., Andreassen, P.R., Wilson, L., Margolis, R.L. Mol. Cell (2004) [Pubmed]
  11. Mad2beta, an alternative variant of Mad2 reducing mitotic arrest and apoptosis induced by adriamycin in gastric cancer cells. Yin, F., Du, Y., Hu, W., Qiao, T., Ding, J., Wu, K., Liu, Z., Fan, D. Life Sci. (2006) [Pubmed]
  12. Expression changes of the MAD mitotic checkpoint gene family in renal cell carcinomas characterized by numerical chromosome changes. Pinto, M., Soares, M.J., Cerveira, N., Henrique, R., Ribeiro, F.R., Oliveira, J., Jerónimo, C., Teixeira, M.R. Virchows Arch. (2007) [Pubmed]
  13. Assignment of mitotic arrest deficient protein 2 (MAD2L1) to human chromosome band 5q23.3 by in situ hybridization. Xu, L., Deng, H.X., Yang, Y., Xia, J.H., Hung, W.Y., Siddque, T. Cytogenet. Cell Genet. (1997) [Pubmed]
  14. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20. Luo, X., Tang, Z., Rizo, J., Yu, H. Mol. Cell (2002) [Pubmed]
  15. Identification of a MAD2-binding protein, CMT2, and its role in mitosis. Habu, T., Kim, S.H., Weinstein, J., Matsumoto, T. EMBO J. (2002) [Pubmed]
  16. Mad2 phosphorylation regulates its association with Mad1 and the APC/C. Wassmann, K., Liberal, V., Benezra, R. EMBO J. (2003) [Pubmed]
  17. Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol. Kienitz, A., Vogel, C., Morales, I., Müller, R., Bastians, H. Oncogene (2005) [Pubmed]
  18. Mitotic checkpoint proteins HsMAD1 and HsMAD2 are associated with nuclear pore complexes in interphase. Campbell, M.S., Chan, G.K., Yen, T.J. J. Cell. Sci. (2001) [Pubmed]
  19. Induction of C-anaphase and diplochromosome through dysregulation of spindle assembly checkpoint by sodium arsenite in human fibroblasts. Yih, L.H., Lee, T.C. Cancer Res. (2003) [Pubmed]
  20. A new Mad2-interacting domain of Cdc20 is critical for the function of Mad2-Cdc20 complex in the spindle assembly checkpoint. Mondal, G., Baral, R.N., Roychoudhury, S. Biochem. J. (2006) [Pubmed]
  21. Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells. Fung, M.K., Cheung, H.W., Ling, M.T., Cheung, A.L., Wong, Y.C., Wang, X. Br. J. Cancer (2006) [Pubmed]
  22. The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. De Antoni, A., Pearson, C.G., Cimini, D., Canman, J.C., Sala, V., Nezi, L., Mapelli, M., Sironi, L., Faretta, M., Salmon, E.D., Musacchio, A. Curr. Biol. (2005) [Pubmed]
  23. DNA polymerase zeta: new insight into eukaryotic mutagenesis and mammalian embryonic development. Zhu, F., Zhang, M. World J. Gastroenterol. (2003) [Pubmed]
  24. The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint. Mapelli, M., Massimiliano, L., Santaguida, S., Musacchio, A. Cell (2007) [Pubmed]
  25. Tpr directly binds to Mad1 and Mad2 and is important for the Mad1-Mad2-mediated mitotic spindle checkpoint. Lee, S.H., Sterling, H., Burlingame, A., McCormick, F. Genes Dev. (2008) [Pubmed]
  26. Structural activation of Mad2 in the mitotic spindle checkpoint: the two-state Mad2 model versus the Mad2 template model. Yu, H. J. Cell Biol. (2006) [Pubmed]
  27. A human REV7 homolog that interacts with the polymerase zeta catalytic subunit hREV3 and the spindle assembly checkpoint protein hMAD2. Murakumo, Y., Roth, T., Ishii, H., Rasio, D., Numata, S., Croce, C.M., Fishel, R. J. Biol. Chem. (2000) [Pubmed]
  28. 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]
  29. WD repeat-containing mitotic checkpoint proteins act as transcriptional repressors during interphase. Yoon, Y.M., Baek, K.H., Jeong, S.J., Shin, H.J., Ha, G.H., Jeon, A.H., Hwang, S.G., Chun, J.S., Lee, C.W. FEBS Lett. (2004) [Pubmed]
  30. Mad2 binding by phosphorylated kinetochores links error detection and checkpoint action in mitosis. Waters, J.C., Chen, R.H., Murray, A.W., Gorbsky, G.J., Salmon, E.D., Nicklas, R.B. Curr. Biol. (1999) [Pubmed]
  31. Anaphase onset does not require the microtubule-dependent depletion of kinetochore and centromere-binding proteins. Canman, J.C., Sharma, N., Straight, A., Shannon, K.B., Fang, G., Salmon, E.D. J. Cell. Sci. (2002) [Pubmed]
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