The cancer prone PCS syndrome : relationship between chromosome dynamics aberration and centrosome amplification(Minireviews with the main theme: "Past, Current and Perspective Studies of the Genome, Chromosomes, and Chromatin")

概要

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Faithful chromosome segregation is maintained by two surveillance mechanisms, one of which is a mitotic spindle checkpoint that delays the onset of anaphase until all chromosomes have established bipolar attachment to the microtubules. Another one is a centrosome because centrosomes define spindle poles and its abnormality leads to chromosome segregation errors and chromosome instability. We and another group recently reported that mutations of BUB1B gene (encoding BubR1, a critical component of the mitotic checkpoint) caused premature chromatid separation (PCS) syndrome, a condition characterized by constitutional aneuploidy and a high risk of childhood cancer. Here we show that the cells from PCS syndrome patients have dysregulated centrosome duplication machinery, resulting in centrosome amplification and multipolar mitosis. Moreover, Wilms tumor tissue derived from a PCS syndrome patient showed high degree of centrosome anplification and aneuploidy. PCS syndrome cells have increased activity of Polo-like kinasel (Plk1), overexpression of which directly causes centrosome amplification. BubR1 localizes to centrosomes and negatively regulates Plk1 activity in normal interphase cells. These results highlight a crucial role for BubR1 in preventing centrosome amplification through negative regulation of Plk1. Thus, PCS syndrome is a "centrosome dysfunctional syndrome" as well as the spindle checkpoint defect.
財団法人染色体学会の論文