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In-Depth Information
initiation of centrosome duplication. For instance, the Ras-MAPK pathway and
Akt (protein kinase B) pathway are both implicated in the regulation of centro-
some duplication (Fukasawa and Vande Woude
1997
; Zeng et al.
2010
; Nam et al.
2010
). Further studies should reveal the underlying mechanisms of the regulation
of centrosome duplication by these pathways.
Overexpression and oncogenic mutation of RTKs are highly common in various
types of cancers. It had been known that chromosomes become destabilized in
cells transformed by oncogenically activated RTKs, but such a phenomenon had
been belittled as an indirect consequence of the continuous firing of growth sig-
nals. However, the recent findings described above indicate that oncogenic acti-
vation of RTKs influences chromosome stability more directly than previously
being thought via induction of centrosome amplification through upregulation of
the Rho-ROCK II pathway and possibly other pathways as well as STAT-
dependent transcription. Considering that chromosome instability plays a critical
role in tumor progression, and centrosome amplification is one of the major causes
of chromosome instability in cancer cells, induction of centrosome amplification
and consequential destabilization of chromosomes should be appreciated as one of
the key oncogenic activities of many RTKs.
10.2 Link Between Activation of Initiation of Centrosome
Duplication and DNA Replication: The Roles
of CDK2-Cyclin E and p53
As described in other chapters, CDK2-cyclin E plays a key role in the initiation of
centrosome duplication (Hinchcliffe et al.
1999
; Lacey et al.
1999
; Tarapore et al.
2002
). In normal cells, initiation of centrosome duplication occurs at the time of S-
phase entry. Because CDK2-cyclin E is also a key triggering factor for DNA
replication (Dulic et al.
1992
; Koff et al.
1992
), the coupling of initiation of
centrosome duplication and DNA replication is at least in part achieved by the late
G1-specific activation of CDK2-cyclin E resulting from the temporal increase of
cyclin E expression. One of the targets of CDK2-cyclin E is nucleophosmin (NPM/
B23). NPM/B23 is involved in the regulation of centrosome duplication both
positively and negatively (Okuda et al.
2000
; Grisendi et al.
2005
; Ma et al.
2006
),
and CDK2-cyclin E-mediated phosphorylation of NPM/B23 on Thr199 residue
simultaneously switches off the negative regulatory function and switches on the
positive regulatory function. By the mediation of the Thr199-phosphorylated
NPM/B23, the CDK2-cyclin E pathway and Rho-ROCK II pathway come together
to trigger initiation of centrosome duplication (Fig.
10.1
). ROCK II is not fully
activated by the Rho binding: Rho binding results in only 1.5-fold increase in the
kinase activity (Amano et al.
1996
). NPM/B23 physically interacts with
Rho-bound ROCK II (the NPM/B23-binding region of ROCK II is located near the
kinase domain, and is masked by the negative regulatory domain in the nascent
