Bub1: escapades in a cellular world.
The spindle assembly checkpoint is an important surveillance mechanism that ensures high fidelity mitotic chromosome segregation. This is accomplished by monitoring whether sister chromatids lack tension or attachment to spindle microtubules. It is mediated by checkpoint complexes or individual proteins that inhibit the ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C) via targeting of the Cdc20 regulatory subunit. The Bub1 kinase is a key spindle checkpoint regulatory protein. Bub1 also plays more pleiotropic roles. Thus, Bub1 is required for assembly of a functional inner centromere, sister chromatid cohesion via targeting of the Shugoshin protein, and metaphase congression. Evidence based on Bub1 mutations in colorectal cancers suggests it might be a driving force in tumorigenesis via generation of chromosomal instability (CIN) and aneuploidy. Recently we reported a surveillance mechanism linking loss of Bub1 to activation of the p53 pathway, specifically premature cell senescence in normal human fibroblasts. Interestingly, SV40 large T antigen (LT) targets Bub1 and this is correlated with oncogenic transformation and compromise of the spindle checkpoint. Future studies on Bub1 combining genetic approaches with analysis of LT perturbations are likely to yield further insight.
Williams
Grace L
GL
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Roberts
Thomas M
TM
Gjoerup
Ole V
OV
D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013539:Simian virus 40 / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases