MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells.
The mitotic checkpoint protein hsMad2 is required to arrest cells in mitosis when chromosomes are unattached to the mitotic spindle. The presence of a single, lagging chromosome is sufficient to activate the checkpoint, producing a delay at the metaphase-anaphase transition until the last spindle attachment is made. Complete loss of the mitotic checkpoint results in embryonic lethality owing to chromosome mis-segregation in various organisms. Whether partial loss of checkpoint control leads to more subtle rates of chromosome instability compatible with cell viability remains unknown. 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. Checkpoint-defective cells show premature sister-chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome mis-segregation events in the absence of these agents. Furthermore, Mad2+/- mice develop lung tumours at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.
Michel
L S
LS
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Liberal
V
V
Chatterjee
A
A
Kirchwegger
R
R
Pasche
B
B
Gerald
W
W
Dobles
M
M
Sorger
P K
PK
Murty
V V
VV
Benezra
R
R
D000705:Anaphase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D020090:Chromosome Segregation; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017353:Gene Deletion; D018816:Genes, cdc; D006801:Humans; D007621:Karyotyping; D008175:Lung Neoplasms / Q000235:genetics*; D064246:Mad2 Proteins; D051379:Mice; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D009687:Nuclear Proteins; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; C577699:Mad2l2 protein, mouse; D009687:Nuclear Proteins; D015739:Nocodazole