Biology Reference
In-Depth Information
mechanisms to favor replication of the viral genome. High-risk HPV-16 E7 can
directly alter E2F-dependent cellular transcription through physical interaction
with E2F1. This interaction results in the pRB-independent enhancement of E2F-
mediated gene transcription (Hwang et al.
2002
). However, the promoter of E2F6,
a transcriptional repressor responsible for directing cell cycle exit, is also E2F-
responsive (Lyons et al.
2006
). The HPV-16 E7 oncoprotein has therefore evolved
to directly associate with E2F6 resulting in inactivation of its transcriptional
repression and maintenance of a replication competent cellular state (McLaughlin-
Drubin et al.
2008
).
Aberrant activation of CDK2 by high-risk HPV-16 E7 further contributes to
alteration of the host cellular environment. The high-risk HPV E7 oncoprotein
functions to disrupt the tight control of CDK2 activation on multiple levels
including upregulation of the E2F-responsive regulatory subunits cyclin A and
cyclin E, direct association with CDK2/cyclin E complexes, enhancing the
enzymatic activities of these complexes and inhibition of the cyclin-dependent
kinase (CDK) inhibitors p21
Cip1
and p27
Kip1
(Funk et al.
1997
; Jones et al.
1997
;
Nguyen and Munger
2008
).
Recently, it has become increasingly evident that high-risk E7 oncoprotein
expression alters components of the host cell epigenetic control machinery. The
first evidence for this came from experiments demonstrating that the HPV-16 and
HPV-31 E7 oncoproteins are capable of associating with histone deacetylases
type-1 and -2 (HDAC-1, and -2) (Brehm et al.
1999
; Longworth and Laimins
2004
). HDACs function as transcriptional repressors by reversing acetyl modifi-
cations of lysine residues on histones. The indirect interaction between oncogenic
HPV-16 E7 and HDACs is mediated by Mi2b, a component of the NURD histone
deacetylase complex (Brehm et al.
1999
). This interaction is dependent on the
integrity of the two Cys-X-X-Cys motifs in the HPV E7 oncoprotein carboxy-
terminus and results in increased E2F-mediated gene transcription from HDAC
responsive promoters (Brehm et al.
1999
). Additionally, high-risk HPV-16 E7 was
also found to associate with histone acetyl transferases (HATs), such as p300 and
pCAF, which function to activate transcription and stimulate cellular proliferation
(Avvakumov et al.
2003
; Bernat et al.
2003
).
High-risk HPV-16 E7 oncoprotein expression can further disrupt host cell
epigenetic control through modulation of histone methylation. Transcriptional
induction of the KDM6A and KDM6B histone 3 lysine 27-specific demethylases
was shown to occur following, and to be dependent on, HPV-16 E7 expression
(McLaughlin-Drubin et al.
2011
). The induction of these two demethylases
reduces the H3K27me3 mark that is necessary for the binding of polycomb
repressive complexes, which in turn enhances the transcription of KDM6A- and
KDM6B-regulated HOX gene expression, including the cervical carcinoma
biomarker p16
INK4A
, promoting epigenetic reprogramming of host cells at the
histone methylation level. Importantly, the enhancement of KDM6A and KDM6B
expression was shown to be independent of pRB-inactivation (McLaughlin-Drubin
et al.
2011
).
