Biology Reference
In-Depth Information
12.9 Models of HPV Oncoprotein-Induced Centrosome
Abnormalities and Malignant Progression
In vitro studies have demonstrated that the HPV-16 E7 oncoprotein disrupts
genomic integrity by directly interfering with centrosome duplication control
(Duensing et al.
2000
). High-risk HPV-16 E7 expression rapidly produces
abnormal centriole numbers in otherwise normal cells prior to the onset of
genomic instability. In contrast, high-risk HPV-16 E6 expressing cells exhibit
centrosome accumulation in cells which are already genomically unstable, often
expressing markers of cellular senescence, and are unlikely to remain in the
proliferative pool or contribute to tumor development (Duensing et al.
2000
).
The in vivo role of HPV-16 E7-induced centrosome abnormalities in malignant
progression is highlighted in a transgenic mouse model of cervical carcinogenesis.
Transgenic mice expressing HPV-16 E7 driven by a cytokeratin 14 promoter and
treated with low doses of estrogen develop numerical centrosome abnormalities in
the cervical mucosa which progress to invasive carcinomas (Riley et al.
2003
). In
contrast, HPV-16 E6 expressing transgenic mice display a comparable level of
numerical centrosome aberrations but develop only low grade cervical lesions that
do not progress to malignant tumors (Riley et al.
2003
). These results suggest that
centrosome aberrations in the context of HPV-16 E7 expression are associated
with a greater risk of malignant progression than in HPV-16 E6 expressing cells.
12.10 The Centriole Multiplication Pathway
Following high-risk HPV-16 E7 expression, supernumerary centrioles appear
rapidly and within a single cell division cycle, suggesting they arise due to direct
disruption of centriole duplication control (Duensing et al.
2007
). This was ini-
tially difficult to reconcile with the prevailing model of centriole duplication
described above, where a single maternal centriole initiates the synthesis of only a
single daughter centriole. Further analysis of HPV-16 E7-induced centriole
abnormalities led to the discovery that the HPV-16 E7 oncoprotein rapidly induces
centriole overduplication through stimulation of a novel centriole duplication
pathway, referred to as centriole multiplication (Duensing et al.
2007
). This
pathway is characterized by a single maternal centriole initiating the simultaneous
synthesis of two or more daughter centrioles. Although, multiciliated epithelial
cells such as those in the trachea and oviduct can rapidly produce hundreds of
centrioles during ciliogenesis through the centriole multiplication pathway, this
had never before been observed in the context of an oncogenic stimulus relevant
for a major human cancer. The mechanism behind the very rapid HPV-16 E7-
mediated induction of centriole multiplication was unknown until recently.
The molecular players involved in the centriole multiplication pathway were
initially
determined
following
the
observation
that
inhibition
of
protein
