Biology Reference
In-Depth Information
the host genome, but most frequently is found at common fragile sites (Thorland
et al.
2000
).
HPV genome integration often results in deletion of a large segment of the viral
genome, usually containing the viral transcriptional regulators E1 and E2 (Baker
et al.
1987
). The E6 and E7 ORFs, however, may remain intact, along with the
LCR, which lies upstream of the integration site within the viral genome.
Disruption of the E1 and E2 viral genes deregulates viral gene transcription and
promotes higher than normal levels of both E6 and E7 gene transcription.
Unrestrained expression of the E6 and E7 oncoproteins induces both genetic and
epigenetic changes in the cellular genome that promotes malignant progression of
host cells. However, overexpression of the HPV-16 E6 and E7 genes is not
necessary for induction of genomic instability, suggesting that the high-risk HPV
E6 and E7 oncoproteins may promote an increased risk of malignant progression
even when their expression is tightly controlled (Duensing et al.
2001
).
12.5 HPV-16 E6 Oncoprotein
The major function of the HPV-16 E7 oncoprotein is to promote a permissive
cellular state for viral replication by disrupting normal cell cycle control mecha-
nisms. The HPV-16 E6 oncoprotein has evolved to complement the function of the
high-risk E7 oncoprotein by preventing the induction of cellular apoptosis due to
aberrant cell cycle regulation. The high-risk E6 oncoprotein prevents apoptosis, in
part, by mediating the degradation of p53 through redirecting a host cell HECT
domain containing E3 ubiquitin ligase, E6-associated protein (E6AP) (Scheffner
et al.
1993
). Low-risk HPV types, such as HPV-6 and HPV-11, also encode an E6
protein. Low-risk E6 proteins can bind to E6AP but cannot mediate the degra-
dation of p53 (Scheffner et al.
1993
). The inability of low-risk E6 to degrade p53
may partially explain the reduced ability of low-risk HPV types to promote car-
cinogenesis (Halbert et al.
1992
).
The high-risk E6 oncoprotein, but not low-risk E6 proteins, contain a PDZ-
domain binding motif, X-(S/T)-X-(V/I/L)-COOH, which may also contribute to
malignancy through interaction with PDZ-domain containing proteins, such
as hDLG, MUPP-1, MAG1-3, and hScrib, resulting in degradation of the PDZ-
protein (Kiyono et al.
1997
; Gardiol et al.
1999
; Lee et al.
2000
; Massimi et al.
2008
). Targeted inactivation of these proteins by oncogenic HPV E6 may disrupt
cell junctions, induce loss of cell polarity, and promote cellular transformation.
In support of this notion, it has been shown that the C-terminal PDZ-binding
domain of high-risk E6 is necessary for the mediation of suprabasal cell prolif-
eration (Nguyen et al.
2003
).
High-risk E6 oncoprotein expression also contributes to cellular immortaliza-
tion through the transcriptional upregulation of hTERT, the catalytic subunit of
human telomerase, and can contribute to telomere maintenance (Klingelhutz et al.
1996
). Enhancement of hTERT expression can occur through several mechanisms
