| Description | called MAD2A (aliases MAD2-LIKE 1, MD2l, HSMAD2); 205 amino acids; molecular weight: 23,509.95; theoretical pI: 5.02 |
| Expression | The MAD2L1 protein is widely expressed in all fetal and adult and fetal tissues studied to date. |
| Localisation | Localizes to the nucleus and associates with unattached kinetochores during after chromosome condensation. |
| Function | Much of what we currently understand about MAD2L1 and its role in the mitotic spindle checkpoint stems from early studies in non-mammalian cells. Several genes have demonstrated critically important, interrelated roles in appropriately responding to aberrant spindle integrity or kinetochore damage by arresting cell cycle progression including BUB (budding uninhibited by benomyl), MAD (mitotic arrest-deficient) genes, additional protein kinase genes, and other cyclin related genes. In budding yeast the mitotic arrest-deficient-2 (MAD2) gene was shown to encode a protein that monitored accurate chromosome segregation via the mitotic spindle checkpoint. The mitotic spindle checkpoint helps regulate cell division to ensure the creation of euploid daughter cells following anaphase and cytokinesis. The checkpoint acts to block cell cycle progression when the mitotic spindle apparatus is not properly assembled or when the kinetochore is not properly attached to the mitotic spindle. The amphibian (Xenopus) homolog of MAD2 was identified and it was demonstrated that the MAD2 protein played a critical role in the normal spindle checkpoint assembly as it associated only with unattached kinetochores in prometaphase and in those cells treated with a microtubule inhibitor, nocodazole. MAD2 was absent from kinetochores in normal cells at metaphase The human homolog of MAD2, MAD2L1, has been isolated through identification of genes that reduced sensitivity to a chemical mitotic spindle assembly inhibiotor, thiabendazole, in yeast that were deficient for a particular kinetochore element , CBF1. The protein encoded by MAD2L1 monitors kinetochore attachments to the mitotic spindle in human cells. Interaction of MAD2L1 and additional checkpoint components with kinetochores unattached to chromosomes blocks the onset of anaphase, preventing missegregation of chromosomes and aneuploidy in resulting daughter cells The nuclear protein encoded by MAD2L1, MAD2A, is a member of the MAD family of proteins that is a critical component of the mitotic checkpoint. MAD2A is required for proper execution of the mitotic checkpoint. When kinetochore-spindle attachment is not completed properly, anaphase is delayed via activation of the mitotic spindle checkpoint. Anaphase is prevented until all chromosomes are properly aligned at the metaphase plate. Normally, the human MAD2A protein localizes as part of a protein complex at unattached kinetochores after chromosome condensation but not after metaphase. Similarly, MAD2A localizes at the kinetochore upon activation of the mitotic spindle checkpoint and mediates cell cycle arrest by associating with CDC20/p55CDC and the anaphase promoting complex (APC) when chromosomes are not properly attached at the kinetochore. Therefore, MAD2A may regulate the activities of the WD40 protein CDC20 that is necessary for progression through anaphase and exit from mitosis. MAD2A reportedly exist in two states, a monomer and a tetramer, both which are capable of binding CDC20. In vitro studies have suggested, but not conclusively established, that only the tetrameric form of MAD2A is capable of inhibiting CDC20 activation of the APC. A yeast 2-hybrid assay using cytoplasmic tails of several a disintegrin and metalloproteinase domain (ADAM) bait proteins, demonstrated that MAD2A interacts strongly with TACE (ADAM17) but not with other ADAMs tested, including ADAM9 which interacts with another MAD family member, the MAD2L2 encoded protein MAD2B. A 35-amino acid stretch of TACE that contains a proline-rich SH3-ligand domain (PXPXXP) has been demonstrated as the interaction site with MAD2A. As noted above, MAD2A is a key protein that functions as part of a larger protein complex that regulates the highly conserved mitotic spindle checkpoint. Appropriate chromosome segregation at anaphase is regulated at least in part by this spindle assembly checkpoint that monitors completion of chromosome-microtubule attachment during metaphase. To further determine the function of Mad2 during normal cell division, Mad2 knockout mice were created and analyzed; day 5.5 embryonic cells lacking Mad2, like mad2 deficient budding yeast cells, grew normally but did not arrest in response to spindle disruption. By d 6.5, the epiblast cells began rapid division associated with widespread chromosome missegregation and subsequent apoptosis. Interestingly, postmitotic trophoblast giant cells survived, however, without Mad2. It was concluded that Mad2 is critical for the spindle assembly checkpoint and accurate chromosome segregation in mitotic mouse cells as well as for embryonic viability, even in the absence of any mitotic spindle damage. Mad2 and the spindle checkpoint in meiosis of S. cerevisiae were further characterized by comparing wildtype and mad2 -/- yeast that lacked normal checkpoint function. In the mad2 deficient yeast cells, meiosis I missegregation was noted to be significantly increased. These studies suggested that mad2 and the spindle checkpoint in budding yeast are critically important for normal meiotic chromosome segregation, despite the fact that normal mad2 function is largely dispensable in wildtype mitosis of budding yeast. |
| Homology | Homologous sequences: Mouse: Mm.43444 Mad2l1; Mm.9648 ESTs, Highly similar to AF072933_1 Mad2-like protein [H.sapiens]; Mm.28402 ESTs, Moderately similar to KIAA0280 [H.sapiens]; Rat: Rn.27237 ESTs, Highly similar to AF072933_1 Mad2-like protein; Rn.34733 ESTs, Weakly similar to mitotic checkpoint component Mad2; Drosophila: Dm.LL.40677 CG2948 CG2948 gene product; Dm.LL.38656 CG17498 CG17498 gene product; Human: Hs.19400 MAD2L2 Related Proteins: H. sapiens: MAD2L2 (27%); M. musculus: MAD2L1 (95%); D. melanogaster: CG17498 (46%); C. elegans: MDF-2 (53%); S. pombe: Mad2p (48%); Spac12d12.09p (26%); S. cerevisiae: Mad2p (43%) [details] |
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