Disruption of Centrosome Duplication Control and Induction of Mitotic Instability by the High-Risk Human Papillomavirus Oncoproteins E6 and E7 - The Centrosome - page 198

including physical interaction of the high-risk E6 oncoprotein with the transcrip-
tion factor, c-MYC, its cofactor Max, and the transcription factor Sp-1, leading to
the transcriptional activation of the hTERT promoter (Liu et al. 2009 ; Katzenel-
lenbogen et al. 2009 ). Further upregulating hTERT activity, the high-risk E6
oncoprotein can promote E6AP-dependent degradation of NFX1-91, a putative
transcriptional repressor of the hTERT promoter (Gewin et al. 2004 ).
12.6 HPV-16 E7 Oncoprotein
The major function of the HPV-16 E7 oncoprotein is to promote the viral life cycle
by disrupting cell cycle control mainly through inactivation of the G 1 /S-phase cell
cycle checkpoint on multiple levels. The HPV-16 E7 oncoprotein accomplishes
this, in part, through binding to and promoting the ubiquitin-mediated proteasomal
degradation of hypophosphorylated RB (pRB), and the related pocket protein
family members p107 and p130, thus releasing the inhibitory complex formed
between pRB and E2Fs and allowing for transcription of S-phase relevant genes
(Dyson et al. 1989 ; Matsushime et al. 1994 ; Resnitzky et al. 1994 ). HPV-16 E7
promotes the degradation of pRB through association with CUL2-based E3
ubiquitin ligase complexes, acting as a substrate-recognition subunit of the E3
ubiquitin ligase complex (Dyson et al. 1989 ; Gonzalez et al. 2001 ; Huh et al.
2007 ). Degradation of pRB occurs in a non-stoichiometric manner allowing even
low levels of E7 protein to promote degradation of pRB. High-risk HPV E7
associates with pRB and its family members through a Leu-X-Cys-X-Glu
(LXCXE) motif located within the CR2 homology domain (Dyson et al. 1989 ).
Additional sequences located in the amino-terminal CR1 homology domain are
necessary for pRB degradation (Huh et al. 2007 ). High-risk HPV-16 E7 has also
been shown to inactivate p600, a pRB-associated protein, contributing to
anchorage-independent growth and cellular transformation (Frisch and Screaton
2001 ; Huh et al. 2005 ).
An important functional difference between low-risk HPV E7 proteins and
high-risk HPV E7 oncoproteins lies in their ability to bind and degrade pRB, p107,
and p130. High-risk HPV-16 E7 binds with a higher affinity to pRB-family
members than do low-risk HPV-6 E7 proteins. In the case of pRB, this difference
maps to a single amino acid change within the pRB-binding domain that confers
high-affinity binding (Heck et al. 1992 ). Low-risk HPV-6 also binds p107 and
p130 with a lower affinity; however, this difference does not map to the same
residue as pRB-binding efficiency (Zhang et al. 2006 ). Moreover, low-risk HPV-6
E7 has recently been shown to destabilize p130, but not pRB or p107, suggesting
that disruption of signaling pathways controlled by p130 are necessary for the
productive stage of the viral life cycle and that pRB and/or p107 degradation are
important for carcinogenesis (Zhang et al. 2006 ).
Besides degradation of pRB, and its related family members, the HPV-16 E7
oncoprotein profoundly disrupts the pRB-signaling axis through several additional