Biology Reference
In-Depth Information
shown that upregulation of E2F activity, which can be equated to the activation of
CDK2-cyclin E, synergistically induces chromosome instability (aneuploidy) with
p53 mutation in lung carcinomas (Karakaidos et al.
2004
). Moreover, considering
that chromosome instability is the driving force for acquisition of more malignant
phenotypes, it is also consistent with the earlier studies showing that concomitant
occurrence of cyclin E overexpression and p53 mutation strongly correlates with
poor prognosis of renal pelvis, ureter, and gastric carcinomas (Furihata et al.
1998
;
Sakaguchi et al.
1998
).
10.4 Other CDK2 and p53 Modulators and Centrosome
Amplification
Because of the involvement of p53 in the regulation of centrosome duplication, the
proteins that control the stability of p53 is expected to participate in the regulation
of centrosome duplication, and aberrant expression/activity of such proteins leads
to centrosome amplification. For instance, Mdm2, an E3 ubiquitin ligase that
promotes degradation of p53 (Haupt et al.
1997
; Kubbutat et al.
1997
), is fre-
quently overexpressed in various types of cancers, especially in those retaining
wild-type p53 (Momand and Zambetti
1997
). When MDM2 is overexpressed in
mouse cells harboring wild-type p53, the level of p53 decreases, leading to effi-
cient induction of centrosome amplification (Carroll et al.
1999
).
Besides the p53-p21 pathway, the activity of CDK2 is also controlled by other
CDK inhibitors, including p27
Kip1
and p16(INK4a). Both p27
Kip1
and p16(INK4a)
have been implicated in the regulation of centrosome duplication. For example,
centrosome amplification associated with DNA damage requires downregulation
of p27
Kip1
in certain cell types such as neuroblastoma cells (Sugihara et al.
2006
).
Loss of p16(INK4a) has also been shown to induce centrosome amplification
(McDermott et al.
2006
). In both cases, uncontrolled activation of CDK2-cyclin E
was detected, which likely contributes to generation of amplified centrosomes.
10.5 Conclusion
It has been known that centrosome duplication occurs in coordination with other cell
cycle-associated events. Thus, it is logical to predict that there are pathways that link
centrosome duplication and the other cell cycle-associated events, including the
RTK activation and DNA replication, and recent studies have started to identify those
pathways. Regarding the molecular link between the RTK activation and centrosome
duplication, the roles of the Rho-ROCK II pathway and STAT pathway were mainly
discussed. However, the activated RTKs transmit the cell cycle signals to many
downstream pathways, and other pathways may play equally important roles to link
the growth stimulation and centrosome duplication, which remains to be determined
