New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 253

Overall, these data suggest that BubR1 may prevent inappropriate centro-
some amplification during interphase by negatively regulating the centro-
some activity of Plk1 ( Izumi et al., 2009 ).
More recently, BubR1 was shown to play an important role in primary
cilia formation ( Miyamoto et al., 2011 ). The primary cilium, whose basal
body is derived from the centriole, is an organelle found on the surface of
most noncycling metazoan cells. In epithelial cells during the G0 phase, cen-
trosomes migrate apically to the cell surface so that the primary cilia can be
assembled ( Nigg and Raff, 2009 ). However, in cells derived from MVA
patients, centrosomes often failed to localize apically and did not generate
cilia. Moreover, knockdown of Medaka fish bubr1 homologue with anti-
sense morpholino oligonucleotides also led to ciliary dysfunction and typical
phenotypes of ciliopathy ( Miyamoto et al., 2011 ). Thus, the role of BubR1
in ciliogenesis seems to be conserved.
The apical docking of the basal body is dependent on proper levels of the
Dishevelled (Dvl) proteins, core components in Wnt signaling, and MVA
mutant cells displayed abnormally high levels of Dvl. Dvl contains a
D-box, and it is targeted for degradation by the APC/C CDH1 after mitotic
exit in G0. Thus, the low levels of BubR1 in MVA mutant cells apparently
lead to the misregulation of APC/C CDH1 in G0 and hence to abnormally
high levels of Dvl ( Miyamoto et al., 2011 ). It is not clear whether the lack
of BubR1 exerts this effect through its failure to regulate the APC/C during
mitosis or whether it also normally intervenes during interphase.
The protein Ajuba was recently found to be associated with microtubules
and centrosomes and to regulate centrosome duplication ( Ferrand et al.,
2009; Sabino et al., 2011 ). Ajuba moreover was reported to interact with
BubR1 in vitro ( Ferrand et al., 2009 ). Interestingly, the medaka homologue
of Ajuba localizes to basal bodies of cilia in growth-arrested medaka hepa-
toma (DIT) cells, and knockdown of Ajuba by antisense morpholinos also
disrupts the positions of the visceral organs and induces abnormal expression
of genes involved in early left-right axis determination ( Nagai et al., 2010 ).
It would be interesting to test if BubR1 and Ajuba may somehow act in a
cooperative manner to regulate the ciliogenesis machinery.
6. BubR1 AND DISEASE
6.1. Mosaic variegated aneuploidy
In humans, mutations in Bub1b , the gene encoding BubR1, were found to
be responsible for many cases of mosaic variegated aneuploidy (MVA), a rare