Biology Reference
In-Depth Information
Ultimately, the HPV-16 E7 oncoprotein profoundly disrupts host cell tran-
scriptional control in order to stimulate cellular proliferation and suppress pro-
grammed cell death. This occurs in a multifaceted manner: broadly by promoting
E2F-activation in both a direct and indirect manner and more precisely through
regulation of the host transcriptome promoted by modifications induced at the
chromatin level.
12.7 HPV Oncoproteins and Genomic Instability
High-risk HPV oncoprotein induced disruption of host cell cycle control and
induction of aberrant S-phase-specific gene expression not only promotes the viral
life cycle but also induces genomic instability, an event which may promote
carcinogenic progression (Duensing and Munger
2004
). This is accomplished
through disruption of the two major tumor suppressors, p53 and pRB, by the two
high-risk HPV oncoproteins E6 and E7, respectively (Scheffner et al.
1993
; Dyson
et al.
1989
). Utilizing high-risk HPV oncoproteins as tools, novel cellular signaling
pathways affected by disruption of p53 and pRB may be determined. As disruption
of these two tumor suppressors is also a hallmark of many non-HPV-associated
carcinomas, these studies may ultimately lead to the discovery of new targets to
prevent malignant progression in both non-HPV and HPV-associated neoplasms.
Mounting evidence suggests that genomic instability may be an important co-
factor in promoting malignant progression. As previously mentioned, multipolar,
specifically tripolar, mitoses are a hallmark of high-risk HPV-associated carci-
nomas (Duensing et al.
2000
). Such a disruption of spindle polarity may conse-
quently promote chromosome missegregation and ultimately aneuploidy (Boveri
2008
). How multipolar spindle poles may arise in HPV-associated lesions will be
discussed below. However, besides aneuploidy, numerical and structural chro-
mosomal instability are also a critical factor for malignant progression. Cytogenic
analyses of HPV-associated lesions have revealed recurring patterns of chromo-
some gains and losses. In particular, gain of chromosome 3q has been linked to the
transition to invasiveness in high-risk HPV-associated lesions (Heselmeyer et al.
1996
). Several other common structural alterations observed in HPV-associated
neoplasms include gains of genetic material on chromosomes 1q, 5p, 6p, and 20q
and losses mapped to chromosomes 2q, 3p, 4, 8p, and 13q (Wilting et al.
2006
;
Bibbo et al.
1989
; Hashida and Yasumoto
1991
).
The role of structural chromosomal abnormalities in high-risk HPV-associated
malignant progression is highlighted by an increased incidence of anaphase
bridges in high-risk HPV-associated lesions (Duensing and Munger
2002
).
Anaphase bridges may form through chromosome fusions at telomeres or double-
stranded DNA breaks (Acilan et al.
2007
) and unrepaired, broken DNA can
promote gene translocations or gene amplifications/deletions, which may provide a
growth advantage to cells through gain of oncogenes or loss of tumor suppressors.
