It was here the most produced metabolite and appeared to co-occur with the other derivatives

conclude that a formal assessment of the role of AURORA B in the checkpoint response will require more pen etrant and selective inhibition of AURORA B.Aneuploidy is observed in 8090% of human cancers and associated with poor clinical outcome, but its role in malignant cell transformation remains ambiguous. To ensure faithful chromosome segregation, eukaryotic cells have developed a surveillance system, the mitotic checkpoint, which delays anaphase onset until all kinetochores are properly attached to microtubules emanating from opposite spindle poles. One of the core components of this checkpoint is Bub1. In prophase, this serine/threonine protein kinase accumulates at unattached kinetochores where it mediates the recruitment of Mad1Mad2 dimers. These Mad1Mad2 dimers produce a diffusible anaphase wait signal consisting of protein complexes of Bub3, BubR1, and Mad2. These complexes bind to and inhibit Cdc20, the Correspondence to Jan van Deursen: [email protected] Abbreviations used in this paper: CAGGS, CMV early enhancer/Oleandrin site chicken -actin; CPC, chromosome passenger complex; HA, hemagglutinin; MEF, mouse embryonic fibroblast; PMSCS, premature sister chromatid separation. activating subunit of the anaphase-promoting complex/cyclosome, an E3 ubiquitin ligase that regulates orderly separation of chromosomes by targeting various cell cycle regulators for degradation by the 26S proteasome at specific mitotic stages. Bub1 not only regulates APC/C activity via kinetochore recruitment of Mad1Mad2, but has also been proposed to inhibit APC/C activity directly through phosphorylation of Cdc20. In addition to the Mad proteins, several other mitotic proteins are dependent on Bub1 for efficient recruitment to unattached kinetochores, including BubR1, Cenp-E, and Sgo1. BubR1 and Cenp-E both function in microtubulekinetochore attachment and failure PubMed ID: to recruit these proteins at unattached kinetochores is known to cause chromosome missegregation. Sgo1, on the other hand, acts to maintain centromeric cohesion of duplicated chromosomes until bi-orientation has been accomplished. The current model is that Bub1 2011 Ricke et al. This article is distributed under the terms of an Attribution NoncommercialShare AlikeNo Mirror Sites license for the first six months after the publication date. After six months it is available under a Creative Commons License. Mutations in Bub1 and other mitotic checkpoint genes are relatively rare in human cancers. On the other hand, deregulation of mitotic checkpoint gene expression seems to occur at much higher incidence. For instance, reduced Bub1 expression has been detected in a subset of lung, colon, and pancreatic tumors. Mouse models mimicking these reductions are prone to aneuploidy and cancer, indicating that Bub1 insufficiency can increase cancer risk. A far more common event in human tumors may be up-regulation of mitotic factors and several studies have found high Bub1 levels in subsets of breast and gastric cancers, and lymphomas. Furthermore, independent studies of diverse tumor types have identified Bub1 as a gene whose up-regulation correlates with poor clinical prognosis. Based on these observations, it is tempting to speculate that there might be a causal relationship between up-regulation of Bub1 and tumorigenesis. However, because Bub1 expression is relatively high in proliferating cells compared with quiescent or differentiated cells, increased Bub1 levels may simply represent an increase in the mitotic