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MAD2  -  spindle checkpoint protein MAD2

Saccharomyces cerevisiae S288c

Synonyms: J1256, Mitotic MAD2 protein, Mitotic spindle checkpoint component MAD2, YJL030W
 
 
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Disease relevance of MAD2

 

High impact information on MAD2

  • We find that Orc2 depletion causes a delay in progression through mitosis, reflecting activation of both the DNA-damage and Mad2-spindle checkpoints [3].
  • Recent experiments shed important insight into how Mad2 molecules bound to centromeres through their association with a protein called Mad1 might be transferred to Cdc20 and thereby inhibit securin's destruction [4].
  • Kinetochores that have not yet attached to microtubules catalyze the sequestration of Cdc20 by an inhibitor called Mad2 [4].
  • MAD1 and MAD2 act in a surveillance mechanism that mediates a metaphase delay in response to nonexchange chromosomes, whereas MAD3 acts as a crucial meiotic timer, mediating a prophase delay in every meiosis [5].
  • Therefore MAD2 and BET2 gene products may physically interact to form a geranylgeranyl transferase complex [6].
 

Biological context of MAD2

  • In addition, the difference between the phenotypes of mad2-1 and mad2-2ts suggests that MAD2 has distinct roles in protein transport and the mitotic feedback control [6].
  • We have cloned the MAD2 gene, which encodes a protein of 196 amino acids that remains at a constant level during the cell cycle [7].
  • These data support the view that the spindle assembly checkpoint encompasses regulation of distinct mitotic steps, including a MAD2-directed block to anaphase initiation and a BUB2-directed block to TEM1-dependent exit [8].
  • Deletion of MAD1 or MAD2 did not affect steady-state nucleocytoplasmic distribution of a classical nuclear localization signal-containing reporter, a nuclear export signal-containing reporter, or Ran localization [9].
  • We conclude that Mad1 and Mad2 are required to detect bipolar orientation and/or tension at kinetochores, whereas Mad3 is not [10].
 

Anatomical context of MAD2

  • The MAD2 branch of the pathway responds to kinetochore microtubule interactions and the BUB2 branch of the pathway operates within the cytoplasm, responding to spindle misorientation [11].
  • Ran GTPase regulates Mad2 localization to the nuclear pore complex [9].
  • The human homolog of MAD2 was isolated and shown to be a necessary component of the mitotic checkpoint in HeLa cells by antibody electroporation experiments [1].
  • Mad1 may anchor Mad2 to the nuclear membrane and regulate its entry into the nucleus [12].
 

Associations of MAD2 with chemical compounds

 

Physical interactions of MAD2

  • Accumulation of Mad2-Cdc20 complex during spindle checkpoint activation requires binding of open and closed conformers of Mad2 in Saccharomyces cerevisiae [15].
  • On the basis of these results and genetic analysis of double mutants, we propose a model in which Mad1p bound to a Nup53p-containing complex sequesters Mad2p at the NPC until its release by activation of the spindle checkpoint [16].
 

Enzymatic interactions of MAD2

  • In addition, Mad2p binds to all of the different phosphorylated isoforms of Mad1p that can be resolved on SDS-PAGE [7].
 

Regulatory relationships of MAD2

  • Budding yeast Bub2 is localized at spindle pole bodies and activates the mitotic checkpoint via a different pathway from Mad2 [17].
  • The Cdc14 liberation from the nucleolus was inhibited by the Mad2 checkpoint and by the Bub2 checkpoint in a different manner when microtubule organization was disrupted [18].
  • Genetic interactions with checkpoint and apc mutants suggest Cdc28 may regulate checkpoint arrest downstream of the MAD2 and BUB2 pathways [19].
 

Other interactions of MAD2

  • Overexpression of BUB1, which interacts genetically with BUB3 and which is involved in the same checkpoint pathway, also rescues the cold sensitivity of tub1-729, but another checkpoint gene, MAD2, does not [20].
  • We demonstrate that Mad3p function is required for the overexpression of Mad2p to result in a metaphase arrest [21].
  • The spindle checkpoint is composed of two independent pathways, one leading to inhibition of the metaphase-to-anaphase transition by checkpoint proteins, including Mad2, and the other to inhibition of mitotic exit by Bub2 [22].
  • CDH1 showed genetic interactions with MAD2 and PDS1, genes encoding components of the mitotic spindle assembly checkpoint that acts at metaphase to prevent premature chromosome segregation [23].
  • RAM2 is also homologous to MAD2, a yeast gene whose product has been implicated in the feedback control of mitosis [14].
 

Analytical, diagnostic and therapeutic context of MAD2

References

  1. Identification of a human mitotic checkpoint gene: hsMAD2. Li, Y., Benezra, R. Science (1996) [Pubmed]
  2. Characterization of regions in hsMAD1 needed for binding hsMAD2. A polymorphic change in an hsMAD1 leucine zipper affects MAD1-MAD2 interaction and spindle checkpoint function. Iwanaga, Y., Kasai, T., Kibler, K., Jeang, K.T. J. Biol. Chem. (2002) [Pubmed]
  3. The Origin Recognition Complex Functions in Sister-Chromatid Cohesion in Saccharomyces cerevisiae. Shimada, K., Gasser, S.M. Cell (2007) [Pubmed]
  4. How do so few control so many? Nasmyth, K. Cell (2005) [Pubmed]
  5. The roles of MAD1, MAD2 and MAD3 in meiotic progression and the segregation of nonexchange chromosomes. Cheslock, P.S., Kemp, B.J., Boumil, R.M., Dawson, D.S. Nat. Genet. (2005) [Pubmed]
  6. The mitotic feedback control gene MAD2 encodes the alpha-subunit of a prenyltransferase. Li, R., Havel, C., Watson, J.A., Murray, A.W. Nature (1993) [Pubmed]
  7. The spindle checkpoint of budding yeast depends on a tight complex between the Mad1 and Mad2 proteins. Chen, R.H., Brady, D.M., Smith, D., Murray, A.W., Hardwick, K.G. Mol. Biol. Cell (1999) [Pubmed]
  8. Saccharomyces cerevisiae BUB2 prevents mitotic exit in response to both spindle and kinetochore damage. Krishnan, R., Pangilinan, F., Lee, C., Spencer, F. Genetics (2000) [Pubmed]
  9. Ran GTPase regulates Mad2 localization to the nuclear pore complex. Quimby, B.B., Arnaoutov, A., Dasso, M. Eukaryotic Cell (2005) [Pubmed]
  10. Bipolar orientation of chromosomes in Saccharomyces cerevisiae is monitored by Mad1 and Mad2, but not by Mad3. Lee, M.S., Spencer, F.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  11. The spindle checkpoint of Saccharomyces cerevisiae responds to separable microtubule-dependent events. Daum, J.R., Gomez-Ospina, N., Winey, M., Burke, D.J. Curr. Biol. (2000) [Pubmed]
  12. Control of localization of a spindle checkpoint protein, Mad2, in fission yeast. Ikui, A.E., Furuya, K., Yanagida, M., Matsumoto, T. J. Cell. Sci. (2002) [Pubmed]
  13. Two complexes of spindle checkpoint proteins containing Cdc20 and Mad2 assemble during mitosis independently of the kinetochore in Saccharomyces cerevisiae. Poddar, A., Stukenberg, P.T., Burke, D.J. Eukaryotic Cell (2005) [Pubmed]
  14. Bet2p and Mad2p are components of a prenyltransferase that adds geranylgeranyl onto Ypt1p and Sec4p. Jiang, Y., Rossi, G., Ferro-Novick, S. Nature (1993) [Pubmed]
  15. Accumulation of Mad2-Cdc20 complex during spindle checkpoint activation requires binding of open and closed conformers of Mad2 in Saccharomyces cerevisiae. Nezi, L., Rancati, G., De Antoni, A., Pasqualato, S., Piatti, S., Musacchio, A. J. Cell Biol. (2006) [Pubmed]
  16. The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint. Iouk, T., Kerscher, O., Scott, R.J., Basrai, M.A., Wozniak, R.W. J. Cell Biol. (2002) [Pubmed]
  17. Budding yeast Bub2 is localized at spindle pole bodies and activates the mitotic checkpoint via a different pathway from Mad2. Fraschini, R., Formenti, E., Lucchini, G., Piatti, S. J. Cell Biol. (1999) [Pubmed]
  18. Mitotic exit network controls the localization of Cdc14 to the spindle pole body in Saccharomyces cerevisiae. Yoshida, S., Asakawa, K., Toh-e, A. Curr. Biol. (2002) [Pubmed]
  19. Mutations in the yeast cyclin-dependent kinase Cdc28 reveal a role in the spindle assembly checkpoint. Kitazono, A.A., Garza, D.A., Kron, S.J. Mol. Genet. Genomics (2003) [Pubmed]
  20. Suppression of a conditional mutation in alpha-tubulin by overexpression of two checkpoint genes. Guénette, S., Magendantz, M., Solomon, F. J. Cell. Sci. (1995) [Pubmed]
  21. Fission yeast Mad3p is required for Mad2p to inhibit the anaphase-promoting complex and localizes to kinetochores in a Bub1p-, Bub3p-, and Mph1p-dependent manner. Millband, D.N., Hardwick, K.G. Mol. Cell. Biol. (2002) [Pubmed]
  22. The role of Cdc55 in the spindle checkpoint is through regulation of mitotic exit in Saccharomyces cerevisiae. Yellman, C.M., Burke, D.J. Mol. Biol. Cell (2006) [Pubmed]
  23. The role of Cdh1p in maintaining genomic stability in budding yeast. Ross, K.E., Cohen-Fix, O. Genetics (2003) [Pubmed]
  24. The dephosphorylated form of the anaphase-promoting complex protein Cdc27/Apc3 concentrates on kinetochores and chromosome arms in mitosis. Topper, L.M., Campbell, M.S., Tugendreich, S., Daum, J.R., Burke, D.J., Hieter, P., Gorbsky, G.J. Cell Cycle (2002) [Pubmed]
  25. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Luo, X., Fang, G., Coldiron, M., Lin, Y., Yu, H., Kirschner, M.W., Wagner, G. Nat. Struct. Biol. (2000) [Pubmed]
  26. Identification of an overlapping binding domain on Cdc20 for Mad2 and anaphase-promoting complex: model for spindle checkpoint regulation. Zhang, Y., Lees, E. Mol. Cell. Biol. (2001) [Pubmed]
 
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