Biology Reference
In-Depth Information
Table 15.1
Genes with known roles in centrosome function/regulation of centrosome number implicated in multiple myeloma oncogenesis
Gene
Known role in centrosome function or regulation of centrosome number
Role in myeloma oncogenesis
AKT1
Active AKT1 expression induces supernumerary centrosomes
(Plo and Lopez
2009
)
Knockdown of Akt1 impairs survival of Akt-dependent MM
lines (Zollinger et al.
2008
)
Aurora-A kinase
Overexpression of Aurora-A induces centrosome amplification
in vitro (Zhou et al.
1998
); Aurora A gives rise to extra
chromosomes through defects in cell division and consequent
tetraploidization (Meraldi et al.
2002
)
Aurora kinase inhibitors inhibits myeloma growth at
nanomolar concentration (Shi et al.
2007
); Aurora-A kinase
RNAi induces apoptotic death in myeloma cells (Evans
et al.
2008
); VX680 induces apoptosis in HMCL (Hose
et al.
2009
); MLN8237, a small molecule Aurora A kinase
inhibitor, inhibits cell proliferation in HMCL (Gorgun et al.
2010
)
BRCA1
BRCA1 localizes to centrosomes (Hsu and White
1998
); cells from
mice lacking full-length BRCA1 show a high frequency of
centrosome amplification (Xu et al.
1999
); BRCA1-dependent
ubiquitination of gamma-tubulin regulates centrosome number
(Starita et al.
2004
)
BRCA1 gene expression upregulated in high CI MM (Chng
et al.
2008
)
BRCA2
Loss of BRCA2 results in centrosome amplification (Tutt et al.
1999
); exogenous expression of NPM-binding region of BRCA2
results in aberrant centrosome amplification (Wang et al.
2011b
)
BRCA2 is located on 13q12; 13q deletions common in MM
(Mohamed et al.
2007
; Fonseca et al.
2009
; Fonseca et al.
2004
; Christensen et al.
2007
; Yuregir et al.
2009
; Wu et al.
2007
); no direct evidence for BRCA2 involvement in
myeloma pathogenesis at present
b-catenin
b-catenin is a component of the intercentrosomal linker and
participates in centrosome separation (Bahmanyar et al.
2008
);
b-catenin participates in centrosome amplification, and mutations
in b-catenin might contribute to the formation of abnormal
centrosomes seen in cancer (Bahmanyar et al.
2010
)
b-catenin small interfering RNA suppresses MM progression
in a xenograft mouse model (Ashihara et al.
2009
); b-
catenin knockdown and overexpression in HMCL led to a
significant decrease and increase in proliferation
respectively (Dutta-Simmons et al.
2009
)
CDK2-Cyclin E
CDK2 & CDK4 are critical mediators of centrosome amplification
in p53-null cells (Adon et al.
2010
)
Although there is no direct evidence that CDK2-Cyclin E is
important for MM pathogenesis, p27, a CDK2-Cyclin E
inhibitor, is implicated in MM; see below
CDK2-Cyclin A
Cyclin D1 overexpression induces centrosome amplification in
hepatocytes and human breast epithelial cells (Nelsen et al.
2005
)
Cyclin D dysregulation is an early unifying pathogenic event in
MM (Bergsagel et al.
2005
); CDK4-Cyclin D1 & CDK6-
Cyclin D2 inactivates Rb in MM and promotes cell cycle
dysregulation (Ely et al.
2005
)
CDK4/CDK6-
Cyclin D
