New Insights into the Role of BubR1 in Mitosis and Beyond - International Review of Cell and Molecular Biology - page 256

on the stability and biochemical activity of BubR1 protein remain to
be determined.
Intriguingly, the protein product of the BCSG1 (breast-cancer-specific
gene 1) also called Synuclein gamma (SNCG), and expressed only by
advanced-stage breast carcinoma cells, reportedly binds BubR1 and causes
its proteasome-dependent degradation ( Gupta et al., 2003 ). In addition,
BRCA1 positively regulates the transcription of BubR1 in the breast cancer
cell line MCF-7 ( Chabalier et al., 2006 ). Moreover, HBx, a viral
oncoprotein encoded by the hepatitis B virus, one of the primary etiological
factors for the development of HCC, was shown to interact with BubR1 in
mammalian cells and to interfere with the binding of BubR1 to Cdc20
thereby affecting the SAC and resulting in the accumulation of lagging chro-
mosomes and chromosomes bridges ( Kim et al., 2008 ). This finding could
account for the previous observation that reported that five out of eight
aneuploidy HCC cell lines exhibit an impaired SAC when treated with
nocodazole or colcemid ( Saeki et al., 2002 ). Interestingly, Tap73, a p53 fam-
ily member, directly binds to BubR1, and the binding of BubR1 to Cdc20
was shown to be impaired in TAp73 / MEFs as well as in HeLa cells
treated with TAp73 siRNA. TAp73 / mice develop spontaneous tumors,
particularly lung adenocarcinomas, and are more sensitive to chemical car-
cinogens. Additionally, decreased TAp73 expression correlates with
increases of SAC protein expression in patients with lung cancer
( Tomasini et al., 2009 ). Collectively, these data suggest that altering the pro-
tein levels of BubR1 or affecting its binding to Cdc20 to induce chromo-
somal aneuploidy may have important consequences for genomic stability
and tumorigenicity.
While mutations in the Bub1b gene encoding BubR1 are relatively rare
in human cancers, several studies have provided evidence that low expres-
sion levels of BubR1 gene could contribute to cancer etiology and progres-
sion. In 31% of examined human colon adenocarcinomas, BubR1 showed a
markedly reduced expression compared to neighboring normal tissues ( Shin
et al., 2003 ). Shichiri et al. (2002) reported that colon carcinomas with
reduced BubR1 mRNA levels were associated with lymph node metastasis
and shorter relapse-free survival after surgery. Another study found reduced
expression of BubR1 (associated with hypermethylation of its promoter) in
several lung cancer cell lines ( Park et al., 2007 ).
On the other hand, there are numerous reports that high levels of BubR1
may be a prognostic marker for tumor recurrence and disease progression.
Colorectal cancers and gastrointestinal cancers show high expression of