New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 254

autosomal recessive syndrome ( Hanks et al., 2004; Matsuura et al., 2006 ).
MVA syndrome, also called premature chromatid separation (PCS) syn-
drome, is characterized by microcephaly, growth, and mental retardation,
and MVA patients are more prone to develop childhood cancers such as
Wilms tumor, rhabdomyosarcoma, and leukemia. At the cellular level,
MVA syndrome is characterized by high levels of mosaic aneuploidy and
PCS. Hanks and coworkers showed that five out of eight MVA families
carry biallelic BubR1 mutations where one truncated BubR1 allele is com-
bined with another allele with a missense mutation ( Hanks et al., 2004 ).
Another study reported that BubR1 expression was reduced by more than
50% in seven MVA families carrying monoallelic BubR1 mutations
( Matsuura et al., 2006 ). As mentioned earlier, missense mutations mapping
in or near the kinase domain were shown to reduce overall BubR1 levels by
destabilizing the protein ( Suijkerbuijk et al., 2010 ).
6.2. Senescence and cell differentiation
Baker and coworkers generated Bub1b H/H hypomorphic mice, expressing
just 10% of normal levels of wild-type BubR1 protein, and found that these
mice develop several phenotypes associated with early aging, including
reduced life span, cachectic dwarfism, muscle atrophy, lordokyphosis, cat-
aracts, loss of subcutaneous fat, impaired wound healing, and infertility
( Baker et al., 2004 ). MEF cells isolated from these Bub1b H/H mice showed
increased senescence after just five passages in culture. Interestingly, BubR1
protein levels in the wild-type mice naturally decrease with age ( Baker et al.,
2004 ), and BubR1 mRNA expression declines along with proliferation
capacity in aged human aortic smooth muscle cells ( Guntani et al., 2011 ).
Collectively, these findings suggest a role for BubR1 in the natural aging
process. Somewhat surprisingly, we do not yet know if the aging is due
to the increased frequency of aneuploidy in these animals, or if it has another
cause. Further investigations will be needed to unravel the molecular path-
way through which BubR1 promotes aging.
One study reported that mice heterozygous for a BubR1 mutation
exhibit abnormally high numbers of megakaryocytes associated with a
50% decrease of platelets in peripheral blood ( Wang et al., 2004 ). The
authors suggested that the decrease in platelet production may be due to
defects in a BubR1-mediated step in the terminal differentiation of the
megakaryocytic progenitor cells into platelets ( Wang et al., 2004 ). Another
study revealed a possible role of BubR1 in the regulation of adult stem cell