Biology Reference
In-Depth Information
genetic alterations including mutations, activations, or deletions of oncogenes,
tumor suppressors, or cell cycle regulators that affect centrosome duplication and
function (Salisbury
2001
).
14.2 Regulation of Centrosomes
14.2.1 Disruption of Nucleophosmin-Mediated Centrosome
Control in Breast Cancer
Centrosome duplication is a process that takes place in S phase in coordination with
DNA duplication. Both events are triggered by the activation of CDK2-cyclin E
(Meraldi et al.
1999
; Mussman et al.
2000
). Several CDK2-cyclin E target proteins
have been identified to be involved in centrosome regulation including nucleo-
phosmin (NPM) a protein that functions as a chaperone in several cellular events and
is frequently mutated in cancer cells (Okuda et al.
2000
; Tokuyama et al.
2001
).
NPM localizes between the paired centrioles and is thought to function in centriole
pairing (Shinmura et al.
2005
). NPM dissociates from the centrosome upon phos-
phorylation by CDK2-cyclin E leading to the separation of the two centrioles, an
initial step in the centrosome duplication cycle. The centrioles are tightly paired
throughout the cell cycle except during the initiation of duplication. Abrogation of
mechanisms underlying centriole pairing, such as depletion of NPM, results in the
generation of extra centrosomes (Grisendi et al.
2005
). In addition, it has been shown
that after being phosphorylated, NPM binds to ROCK2, a member of the Rho-
associated coiled containing protein kinase family, which is overexpressed in many
cancers including breast cancer. Binding of phosphorylated NPM to ROCK2 acti-
vates it at the centrosomes leading to the initiation of centrosome duplication (Ma
et al.
2006
). Recently, NPM and ROCK2 have been shown to form a complex with
BRCA2. This complex functions in maintaining the integrity of centrosome dupli-
cation. Inhibition of the NPM-BRCA2 interaction results in supernumerary cen-
trosomes, a phenotype that would ultimately cause genetic instability and
tumorigenesis. In addition, the loss of association between NPM and BRCA2 might
play an important role in familial breast carcinogenesis since many missense
mutations have been reported in the NPM binding region of BRCA2 in the hered-
itary breast and/or ovarian cancer families (Wang et al.
2011
).
14.2.2 Control of Centrosomes by Cyclin A in Cancer
In addition to cyclin E, CDK2 forms a complex with cyclin A, which has also
been implicated in the regulation of centrosome duplication. It has been shown that
cyclin A promotes centriole overduplication in S phase-arrested cells through a
