New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 255

differentiation. Inhibition of BubR1 in human adipose-derived mesenchy-
mal stem cells (ASCs) blocked the potentiality of the cells to differentiate
into adipocytes and moreover induced cellular senescence which was inde-
pendent of the levels of p16 INK4A protein (a Cdk1 inhibitor and marker for
senescence) ( Lee et al., 2009a ). Moreover, endogenous BubR1 levels
declined in conjunction with the number of ASCs cell passages and similarly
correlated with the loss of differentiation potential with passage number. In
addition, the observed decline in BubR1 expression was mediated by the
methylation of its promoter. The authors suggest that BubR1 may contrib-
ute to the maintenance of the differentiation potential and delay cellular
senescence in proliferating ASCs. The underlying mechanism which may
explain how BubR1 regulates adult stem cell differentiation and prevents
cellular senescence remains to be determined.
6.3. BubR1 and cancer
Several genetic studies in mice have demonstrated that a defective SAC can
lead to aneuploidy and tumorigenesis. More specifically, BubR1 þ / mice
treated with the carcinogen DMBA develop more rapidly tumor in colon
and lungs compared to wild-type DMBA-treated mice ( Dai et al., 2004 ).
Moreover, mice doubly heterozygous for BubR1 and Apc-min (adenomatous
polyposis coli) mutant alleles develop more spontaneous highly malignant
colonic tumors than the Apc Min/þ mutant mice alone ( Rao et al., 2005 ).
Additionally, spontaneous Bub1 and BubR1 mutations were found associ-
ated with the development of thymic lymphomas in homozygous Brca2
mutant mice ( Suijkerbuijk et al., 2012a ).
In certain human cancers with aneuploidy, genetic or epigenetic muta-
tions have been identified in BubR1. While impairment of the SAC is fre-
quently associated with tumorigenesis, inactivation of BubR1 by somatic
mutations in the Bub1B is a rare event in bladder cancer ( Olesen et al.,
2001 ) and other human malignancies such as lung cancers, aneuploidy breast
cancer cell lines, thyroid cancer cell lines, and hepatocellular carcinoma
(HCC) cell lines ( Haruki et al., 2001; Myrie et al., 2000; Ouyang et al.,
2002; Saeki et al., 2002 ). Moreover, two heterozygous point mutations,
one homozygous point mutation, and one with a 47-bp deletion in the
Bub1b gene were detected in 4 of 10 cases of adult T-cell leukemia/lym-
phoma, and one nonsense BubR1 mutation was detected in 1 out of 8 B-cell
lymphomas ( Ohshima et al., 2000 ). However, the effects of these mutations