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in U2OS and HeLa cells as a consequence of acentriolar pole formation and centriole
disengagement (Dai et al. 2009 ).
CENPA (Hori et al. 2008 ), the centromere-specific histone H3 variant, CENPT
(Hori et al. 2008 ), a component of the linker structure connecting the centromere
with outer kinetochore components, sororin (also known as cell division cycle
associated 5 (CDCA5)) (Schmitz et al. 2007 ), a protein involved in sister chro-
matid cohesion, and the augmin complex (Lawo et al. 2009 ), which promotes
microtubule-dependent MT amplification within the mitotic spindle, are necessary
for centrosome clustering as well (Kwon et al. 2008 ; Leber et al. 2010 ). Similar to
haspin depletion, knockdown of augmin complex components leads to the for-
mation of acentriolar spindle poles and centrosome fragmentation in addition to
centrosomal declustering (Leber et al. 2010 ; Lawo et al. 2009 ; Uehara et al. 2009 ;
Einarson et al. 2004 ; Wu et al. 2008 ). Most recently, hepatoma upregulated protein
(HURP) has been shown to be required for centrosome clustering in cells with
supernumerary centrosomes as well (Breuer et al. 2010 ). This observation is
noteworthy as HURP serves as an attachment- and tension-sensitive kinetochore
MT stabilizing factor during mitosis (Koffa et al. 2006 ; Sillje et al. 2006 ; Wong
and Fang 2006 ).
Together, these findings support the notion that loss of centromere tension
results in centrosome declustering. Indeed, when pulling forces are measured
directly across multipolar spindles in cancer cells with supernumerary centro-
somes, depletion of NDC80, CPC and augmin complexes or SGOL1 result in
substantially reduced spindle tension, as indicated by shorter interkinetochore
distances and BUBR1 labeling of kinetochores in multipolar metaphase cells
(Leber et al. 2010 ; Uehara et al. 2009 ). Also, knockdown of haspin has been shown
to reduce tension at sister kinetochores (Dai et al. 2009 ). However, these data also
suggest that at least some of the proteins involved in the clustering of supernu-
merary centrosomes might contribute to centriole cohesion and bipolar spindle
formation in cells with a regular centrosome content as well.
Several of the proteins of the chromosomal passenger and NDC80 complexes
including aurora B, survivin, borealin, NUF2 and HEC1 as well as sororin and
HURP have been found to be overexpressed in a wide variety of cancer types
(Carmena and Earnshaw 2003 ; Bischoff et al. 1998 ; Adams et al. 2001 ; Altieri
2003 ; Chang et al. 2006 ; Hayama et al. 2006 ; Ferretti et al. 2010 ; Nguyen et al.
2010 ; Tsou et al. 2003 ). Furthermore, overexpression of highly expressed in cancer
1 (HEC1), a component of the NDC80 complex as well as aurora B have been
implicated in tumor formation in mouse models (Diaz-Rodriguez et al. 2008 ;
Nguyen et al. 2009 ). These findings have already led to the development of potent
and selective inhibitors of aurora B kinase which are currently in early clinical
trials in patients with different kinds of malignancies (Taylor and Peters 2008 ).
Taken together, these data suggest that proteins involved in centrosome clustering
in cancer cells with supernumerary centrosomes are frequently overexpressed in
human cancers, suggesting that clustering of extra centrosomes into a bipolar
spindle
array
might
indeed
be
important
for
cancer
cell
survival
and/or
progression.
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