Biology Reference
In-Depth Information
Additionally, genomic instability is an early event in HPV-associated malignant
progression being observed in pre-invasive high-risk HPV-associated lesions
(Duensing et al.
2001
). Several lines of evidence show that expression of HPV-16
E6 and E7 by themselves can independently induce structural chromosomal
instability. Further, both the HPV-16 E6 and E7 oncoproteins have independently
been shown to relax mitotic checkpoints (Thomas and Laimins
1998
), which may
be activated in response to altered DNA structures (Mikhailov et al.
2002
),
promoting
polyploidization
and
possibly
predisposing
cells
to
aneuploidy
(Heilman et al.
2009
; Southern et al.
2004
).
Centrosome abnormalities have been detected in a wide range of malignant
tumors including breast, prostate, colon, and cervical cancer, and compelling
evidence suggests that centrosome abnormalities can disrupt mitotic spindle
polarity, drive progressive loss of genomic stability, and promote malignant pro-
gression. Centrosome overduplication has been observed in cells expressing epi-
somal HPV-16 genomes (Duensing et al.
2001
). This observation strongly
underscores that viral integration and overexpression of the high-risk HPV
oncoproteins E6 and E7 is not required for the induction of centrosome abnor-
malities and that centrosome aberrations are early alterations in high-risk HPV-
associated malignant progression.
Determining the pathways that are activated by HPV oncoprotein expression
leading to centrosome overduplication, cell division errors, and ultimately aneu-
ploidy will be important in understanding and preventing the earliest steps in
malignant progression.
12.8 The Centrosome
The centrosome is a crucial cellular organelle, responsible for organizing the
microtubule network in most mammalian cells and coordinating bipolar spindle
pole formation during mitosis (Schatten
2008
). The centrosome consists of two
centrioles, barrel-shaped microtubule-based cylinders, embedded in a pericentri-
olar material (Loncarek et al.
2008
). The two centrioles are distinct in age and
composition, consisting of an older maternal centriole characterized by distal and
subdistal appendage proteins which function to anchor and nucleate microtubules,
and a younger daughter centriole which has not yet associated with appendage
proteins (Azimzadeh and Bornens
2007
). In order to generate two spindle poles,
the single centrosome of a non-dividing cell must duplicate precisely once, and
only once, prior to mitosis in order to ensure faithful cell division.
Centrosome duplication begins during late mitosis/early G
1
-phase of the cell
division cycle, when the two pre-existing centrioles of the single centrosome
disengage through the action of polo kinase 1 (PLK1) and separase, and move into
a near parallel position (Tsou et al.
2009
). This step is followed by recruitment of
polo-like kinase 4 (PLK4) to the wall of the maternal centriole at the site of
daughter centriole synthesis (Habedanck et al.
2005
; Kleylein-Sohn et al.
2007
).
