Biology Reference
In-Depth Information
continued stimulation of CDK2 activity (Duensing et al.
2006
). CDK2-cyclin A
complex cannot, however, initiate duplication of centrosomes during the normal
cell cycle but in prolonged S phase-arrested cells, cyclin A promotes the redu-
plication of centrosomes (Duensing et al.
2007
). Abnormal levels of cyclin A are
frequently detected in human cancers and these abnormal levels may have a
crucial role in centriole overduplication and amplification, which eventually might
be a contributing factor to tumorigenesis (Duensing et al.
2007
; Faivre et al.
2002
).
Since CDK-cyclin controls the duplication of centrosomes, many proteins that
control the activity of the CDK2/Cyclin A complex may also play a role in the
regulation of centrosome duplication (Fukasawa
2007
). One example is p21,
which is a negative regulator of the CDK2 activity. p21 is regulated by p53 which
is one of the proteins that have been implicated in the development of centrosome
defects seen in human breast tumors (Salisbury
2001
). It has been shown that cells
lacking p53 are capable of undergoing centrosome reduplication even when DNA
synthesis is inhibited resulting in centrosome amplification (Balczon et al.
1995
;
Fukasawa et al.
1996
). Inhibition of DNA synthesis occurs under physiological
stress irrespective of the p53 status (Fukasawa
2007
). Normally, p53 is stabilized
under such conditions through the inhibition of MDM2, an E3 ubiquitin ligase that
promotes the degradation of the p53 protein. Stabilization of p53 will result in the
upregulation of p21 that will inhibit the CDK2-cyclin complexes thus inhibiting
the initiation of centrosome reduplication. Cells lacking p53, however, will have
unrestrained activation of CDK2 which in turn will trigger centrosome redupli-
cation leading to the formation of extra centrosomes.
In addition to regulating centrosome duplication through the p53-p21 pathway,
p53 has been shown to localize to the centrosome where it participates in the
regulation of duplication independent of its transactivation function through a
mechanism that is yet to be identified (Fukasawa
2007
; Morris et al.
2000
;
Shinmura et al.
2007
). Mutant p53 protein incapable of transactivating target genes
can still control centrosome duplication if the centrosome localization is retained.
Thus, regulation of p53 stability in general is important in the regulation of cen-
trosome duplication. Overexpression of MDM2, as seen in cancers, for example,
will promote the degradation of p53 causing centrosome amplification (Carroll
et al.
1999
; Vargas et al.
2003
).
14.2.3 Polo-like Kinases and Aurora Kinases in
Centrosome Regulation
Several kinases involved in the regulation of the cell cycle are also known to be
involved in the regulation of centrosome duplication and these include: the polo-
like kinases (Plks), Aurora kinases, and NIMA-related kinases (NEK2). Plks are
centrosomal kinases that control the entry into mitosis (Barr et al.
2004
). Plks are
known to be overexpressed in cancers, and their overexpression correlates with
increased aggressiveness of the disease (Sankaran and Parvin
2006
; Takai et al.
