Cancer Research · 2004 · 293 citations · 16 references
Life SciencesCell BiologyOncologyCarcinogenesisMolecular OncologyTumor ProgressionCancer Genomic InstabilityCancer ProgressionCell Cycle ControlCell Cycle SignalingCell-cycle CheckpointsCell-cycle RegulationCell-cycle Checkpoint RegulationGenetic InstabilityLoss-of-function MutationsMitotic Checkpoint DefectsRna Interference-mediated SuppressionSecurin RegulationTumor Suppression MechanismsTumor Suppression Pathways
A compromised spindle checkpoint is thought to play a key role in genetic instability that predisposes cells to malignant transformation. Loss of function mutations of BubR1, an important component of the spindle checkpoint, have been detected in human cancers. Here we show that BubR1(+/-) mouse embryonic fibroblasts are defective in spindle checkpoint activation, contain a significantly reduced amount of securin and Cdc20, and exhibit a greater level of micronuclei than do wild-type cells. RNA interference-mediated down-regulation of BubR1 also greatly reduced securin level. Moreover, compared with wild-type littermates, BubR1(+/-) mice rapidly develop lung as well as intestinal adenocarcinomas in response to challenge with carcinogen. BubR1 is thus essential for spindle checkpoint activation and tumor suppression.
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Mutations of mitotic checkpoint genes in human cancers
Daniel P. Cahill, Christoph Lengauer, Jian Yu et al. · Nature · 1998 · 1.5K citations
Life Sciences, Genetics, Oncology +14