HPV E6 and E7 genes encode low molecular weight proteins of about, respectively, 150 and 100 amino acids (Fig. 10). It has been shown that expression of E6 and E7 from high-risk HPV types is necessary and sufficient Tanespimycin concentration to immortalize primary keratinocytes, abrogates DNA damage responses, causes genomic instability, and induces epithelial cell hyperplasia (Ghittoni et al., 2010, Hellner and Munger, 2011 and Moody and Laimins, 2010). HPV E6 and E7 proteins do not have intrinsic enzymatic activity but function by associating with several cellular proteins resulting in the alteration of various host cellular pathways. Specific interactions of E6 and
E7 with key cell cycle regulatory proteins [namely E6 with the tumor suppressor protein p53 and E7 with the Rb family of pocket proteins] are responsible for the potential oncogenicity of the high-risk HPV types (Fig. 11A). An important function of p53 is to induce the expression of genes that alter cell cycle progression in G1/S phase in response to DNA damage. Crucial host cell targets of the high-risk E6 protein include many PDZ domain-containing proteins involved in cell–cell contact, communication
and polarity (Howie et al., 2009). The Rb family of proteins control the transition at the G1/S phase of the cell cycle by binding Buparlisib order and regulating the activity of the E2F family of transcription factors. As a consequence of these interactions, E7 stimulates quiescent cells to re-enter S-phase while E6 prevents cellular growth arrest or DNA-damage induced apoptosis (Fig. Orotidine 5′-phosphate decarboxylase 11B). In contrast to PyV LT-ag that inactivates Rb/E2F complexes by stoichiometric association with Rb, high-risk HPV E6 and E7 proteins target, respectively, p53 and Rb for ubiquitin-mediated proteosomal
degradation (Pim and Banks, 2010, McLaughlin-Drubin and Munger, 2009, Yugawa and Kiyono, 2009, Moody and Laimins, 2010 and Miller et al., 2012). E6 associates with the cellular E3 ubiquitin ligase E6-associated protein (E6AP) and the E6/E6AP complex binds p53 and induces its specific ubiquitinylation and subsequent degradation by the proteasome (Fig. 11). High-risk HPV E7 mediates degradation of Rb by a mechanism involving association with and reprogramming of the cullin 2 (CUL2) ubiquitin ligase complex, resulting in the release of active E2F transcription factor which in turn activates the transcription of genes encoding proteins (such as cyclin E and cyclin A) necessary for cell cycle progression (Fig. 11). One member of the RB family, p130, appears to be an important target for E7 in promoting its proteosome-mediated destruction and S-phase entry. Recent evidence indicates that p130 regulates cell-cycle progression as part of a large complex named DREAM (DP, Rb-like, E2F and MuvB). In addition, it was demonstrated that high-risk HPVs can bind to MuvB core complex and activate gene expression during the G2 and M-phase of the cell cycle.