New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 258

leads to the generation of multiple tumors ( Sotillo et al., 2007 ). Moreover,
overexpression of Hec1 in an inducible mouse model results in SAC hyp-
eractivation and is sufficient to generate tumors in vivo ( Diaz-Rodr´guez
et al., 2008 ). Nonetheless, further research will definitely be necessary to
clarify the clinical significance of BubR1 overexpression in cancer tissues.
7. CONCLUDING REMARKS
Great advances have been made in the elucidation of the roles of
BubR1 in mitotic cycle regulation in the past two decades. BubR1 is now-
adays emerging as an important regulator of various mitotic and nonmitotic
processes ranging from SAC function, K-MT attachments, DDR, centro-
some amplification, cilia formation, meiotic progression, and even develop-
mental processes such as hematopoiesis and adult stem cell differentiation.
Nevertheless, our understanding of the molecular mechanisms by which
BubR1 regulates many of these cellular functions is still incomplete and
awaits further detailed investigation. Moreover, despite the fact that abun-
dant phenotypic information supports the correlation of BubR1 expression
with cancer initiation and progression, little is known about the underlying
mechanisms by which BubR1 expression levels may lead to oncogenic
transformation and tumorigenesis.
To what extent are the nonclassical roles attributed to BubR1 in fact
mediated by its known activity in regulating APC/C Cdc20 ? How might
BubR1 affect the activity of APC/C Cdh1 in ciliogenesis and meiosis? It will
be important to attempt to generate new separation of function mutations
that might specifically affect a subset of these newly described functions.
BubR1's additional roles in meiosis also need more study. The different
phenotypes ascribed to BubR1 depletion in oocytes need to be correlated
with knockdown efficiencies in individual oocytes. A clear understanding
of the roles of BubR1 for regulating entry and progression through oocyte
meiosis I and meiotic SAC control will only come from the thorough anal-
ysis of a conditional oocyte-specific invalidation of BubR1, such as have
been used for other SAC components ( Hached et al., 2011; McGuinness
et al., 2009 ). BubR1 seems not to be required for CSF arrest in meiosis
II ( Tsurumi et al., 2004 ), but it remains without doubt that the generation
of healthy, fertilizable oocytes depends on the presence of functional BubR1.
Whether mammalian BubR1 possesses real kinase activity remains to be
fully resolved. A BubR1 “KD” mouse model in which the kinase domain
mutation does not compromise overall protein stability would be highly