High impact information on Mad2l1

• Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2 [1].
• In contrast, the postmitotic trophoblast giant cells survive without Mad2 [1].
• To determine the function of the mitotic checkpoint protein Mad2 during normal cell division and when mitosis goes awry, we have knocked out Mad2 in mice [1].
• MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells [2].
• Here we report that deletion of one MAD2 allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts [2].

Biological context of Mad2l1

• Consistently, reconstitution of Mad2 in Brca1(Delta11/Delta11) cells partially restored the spindle checkpoint and attenuated apoptosis [3].
• The end of prometaphase is correlated with checkpoint inactivation and disappearance of MAD2L1 (MAD2) and RSN (CLIP-170) proteins from kinetochores [4].
• Disruption of Mad2, BubR1, Bub3 or Rae1 in mice results in substantial aneuploidy in somatic tissues, but whether these genes are equally important for accurate chromosome segregation during meiosis has not yet been established [5].
• We conclude that the mitotic checkpoint is not essential for viability per se and that a CIN phenotype can be established in culture through the inactivation of both the Mad2- and p53-dependent checkpoint pathways [6].
• Second, the absolute rate of chromosome missegregation may be increased by alterations in the levels of two proteins, separase and Mad2, which are important for maintaining chromosomal segregation and the normal spindle checkpoint during mitosis [7].

Anatomical context of Mad2l1

• Our study shows for the first time that a functional Mad2-dependent spindle checkpoint exists during the first meiotic division in mammalian oocytes [8].
• In contrast, the microtubule stabilizer taxol induced the loss of Mad2 from the majority of the first-division-metaphase kinetochores in which it was normally present in untreated cells [9].
• Double labelling immunofluorescence with MAD-2 and a mouse monoclonal antibody against vimentin, the intermediate filament protein of cells of mesenchymal origin, showed coincidental staining which was distinct from that seen with antibodies against other cytoskeletal proteins [10].

Associations of Mad2l1 with chemical compounds

• Disruption of the male meiotic spindles with the microtubule depolymerizing agent nocodazole resulted in the appearance of Mad2 at nearly all kinetochores [9].
• MAD2 cross-reacts to varying degrees with anthracycline compounds such as some DXR analogues and derivatives, but does not recognize anthracene and anthraquinone structures, with the exception of weakly reacting Mitoxantrone [11].
• The results of northern blot analysis for small proline-rich protein 2 (Sprr2), 17beta-hydroxysteroid dehydrogenase type 2 (17betaHSD-2), high mobility group 2 (Hmg2), mitotic checkpoint component 2 (Mad2) and an EST AW555366 mRNA were consistent with that of microarray analysis [12].

Co-localisations of Mad2l1

• Confocal microscopy demonstrated that Mad2 colocalized with c-Kit in the cytoplasm of MO7e cells [13].

Other interactions of Mad2l1

• Similar results were obtained using dominant-negative forms of Mad2 and BubR1, as well as checkpoint resistant dominant APC/C activating forms of Cdc20 [14].
• Generating chromosome instability through the simultaneous deletion of Mad2 and p53 [6].

Analytical, diagnostic and therapeutic context of Mad2l1

• The increase in Mad2 protein was observed also at the cellular level by immunohistochemistry [7].
• Real-time PCR and laser scanning confocal microscopy showed that we successfully downregulated MAD2 transcript and protein expression [15].

References