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Review
. 2017 Mar 2:231:56-75.
doi: 10.1016/j.virusres.2016.10.017. Epub 2016 Nov 8.

The human papillomavirus E7 oncoprotein as a regulator of transcription

Affiliations
Review

The human papillomavirus E7 oncoprotein as a regulator of transcription

William K Songock et al. Virus Res. .

Abstract

High-risk human papillomaviruses (HPVs) encode oncoproteins which manipulate gene expression patterns in the host keratinocytes to facilitate viral replication, regulate viral transcription, and promote immune evasion and persistence. In some cases, oncoprotein-induced changes in host cell behavior can cause progression to cancer, but a complete picture of the functions of the viral oncoproteins in the productive HPV life cycle remains elusive. E7 is the HPV-encoded factor most responsible for maintaining cell cycle competence in differentiating keratinocytes. Through interactions with dozens of host factors, E7 has an enormous impact on host gene expression patterns. In this review, we will examine the role of E7 specifically as a regulator of transcription. We will discuss mechanisms of regulation of cell cycle-related genes by E7 as well as genes involved in immune regulation, growth factor signaling, DNA damage responses, microRNAs, and others pathways. We will also discuss some unanswered questions about how transcriptional regulation by E7 impacts the biology of HPV in both benign and malignant conditions.

Keywords: Cell cycle control; E7; Histone deacetylase; Innate immunity; Transcription factor; pRb family.

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Figures

Figure 1
Figure 1
a. The CR1 (blue), CR2 (red) and CR3 (green) domains of E7, along with the zinc-coordinating CXXC motifs (yellow). b. Sites of interaction in E7 with known transcriptional regulators. Numbers represent amino acid positions. Factors that are not involved in transcription or whose binding sites in E7 have not been mapped by mutation are not shown. In some cases binding is reduced (indicated “red”) or increased (indicated “incr”) by mutation of a specific residue. The location of the NLSs (blue bars) and NES (pink bar) are indicated (Knapp, McManus et al. 2009; Eberhard, Onder et al. 2013). Residues colored red are important for dimerization and residues shaded grey are important for cullin 2 binding (Huh, Zhou et al. 2007; Todorovic, Hung et al. 2012).
Figure 2
Figure 2
A simplified depiction of promoter activation. a. Repressed or closed chromatin prevents the binding of transcriptional regulators to the promoter region, in part because of the tight inter-nucleosomal interactions between histone tails. b. Binding of pioneer transcription factors results in the recruitment of histone and chromatin modifying enzymes, or co-activators (co-act), which modify histone tails and chromatin structure to make it more accessible for binding of other protein complexes. c. In active chromatin, additional transcription factors and co-activator proteins are recruited, including the Mediator complex, which recruits the GTFs and Pol II close to the transcriptional start site to form a pre-initiation complex. Through the action of the GTFs, the pre-initiation complex transitions to active transcription.
Figure 3
Figure 3
Regulation of chromatin structure by E7. a. E7 can bind to HDACs and displace them from promoters, such as the E2F2 promoter (Longworth, Wilson et al. 2005). E7 can also displace HDACs from binding to transcription factors, such as HIF1α (Bodily, Mehta et al. 2011). b. Alternatively, E7 can recruit HDACs to promoters in a transcription factor-specific manner, as in the case of MHC-I and TLR9 (Park, Kim et al. 2000; Um, Rhyu et al. 2002; Hasan, Zannetti et al. 2013). c. E7 can bind to HAT co-activators and inhibit their activity. pCAF, p300/CBP, Skip, and SRC are examples (Prathapam, Kuhne et al. 2001; Huang and McCance 2002; Avvakumov, Torchia et al. 2003; Bernat, Avvakumov et al. 2003; Baldwin, Huh et al. 2006; Fera and Marmorstein 2012; Jansma, Martinez-Yamout et al. 2014). Binding of E7 to HATs results in the inhibition of the interleukin 8 (IL8) gene (Huang and McCance 2002) and possibly contributes to the inhibition of p53-mediated transcription (Bischof, Nacerddine et al. 2005; Fera and Marmorstein 2012). E7 can also upregulate transcriptional co-activator Sirt1 (Langsfeld, Bodily et al. 2015). E7 can either promote or prevent promoter DNA methylation by DNMTs (Laurson, Khan et al. 2010; Chalertpet, Pakdeechaidan et al. 2015; Cicchini, Westrich et al. 2016; Yin, Wang et al. 2016). d. PRCs inhibit transcription by recruiting histone methyltransferases (MTases) to promoters. E7 suppresses the expression of PRC components and upregulates the demethylase enzymes KDM6A and KDM6B (Hyland, McDade et al. 2011; McLaughlin-Drubin, Crum et al. 2011).
Figure 4
Figure 4
Regulation of pocket proteins by E7. a. E7 can bind to pocket proteins and target them for degradation, thus facilitating transcription by activating E2Fs (green)(Munger, Werness et al. 1989; Barbosa, Edmonds et al. 1990; Huang, Patrick et al. 1993; Chien, Parker et al. 2000; Dong, Caldeira et al. 2001; Helt and Galloway 2001). b. E7 can also displace pocket protein binding to E2Fs without targeting them for degradation (Chellappan, Kraus et al. 1992; Gonzalez, Stremlau et al. 2001; Collins, Nakahara et al. 2005). c. Inhibitory E2Fs (red), in combination with pocket proteins, can repress E2F dependent promoters. In addition to targeting pocket proteins for degradation, E7 can cause an exchange of activating E2Fs for inhibitory E2F complexes, upregulating gene expression (Longworth, Wilson et al. 2005; McLaughlin-Drubin, Huh et al. 2008). d. DREAM complexes are repressive complexes associated with pocket proteins, inhibitory E2Fs, and MuvB. E7 can cause the disruption of DREAM complexes and recruitment of B-Myb to associate with MuvB and activate mitotic gene expression (Nor Rashid, Yusof et al. 2011; Sadasivam and DeCaprio 2013; Fischer, Quaas et al. 2014; Pang, Toh et al. 2014).
Figure 5
Figure 5
Impact of E7 on transcription factor function. E7 can activate some transcription factors by stimulating upstream signaling pathways. STAT5 (Hong and Laimins 2013) and HIF1 (Wang, Zhan et al. 2014) are two examples. E7 can also inhibit upstream signaling pathways, reducing the function of other transcription factors, including STAT1, NFκB, SMAD2/3, and IRF1 (Perea, Lopezocejo et al. 1997; Mi, Borger et al. 2000; Nees, Geoghegan et al. 2001; Spitkovsky, Hehner et al. 2002; Murvai, Borbely et al. 2004; Hypes, Pirisi et al. 2009; Li, Zhan et al. 2009; Vandermark, Deluca et al. 2012; Hasan, Zannetti et al. 2013; Zhou, Chen et al. 2013; Zhou, Chen et al. 2013; Lau, Gray et al. 2015). E7 can interfere with nuclear localization of STAT1 and NFκB (Perea, Lopezocejo et al. 1997; Nees, Geoghegan et al. 2001; Spitkovsky, Hehner et al. 2002; Li, Zhan et al. 2009; Zhou, Chen et al. 2013; Zhou, Chen et al. 2013). E7 can directly bind to and stimulate transcription factors, including E2F1, B-Myb, c-Myc, and c-Jun (Antinore, Birrer et al. 1996; Hwang, Lee et al. 2002; Wang, Chang et al. 2007; Pang, Toh et al. 2014). Alternatively, E7 can bind and inhibit transcription factors including E2F6, SMAD2/3, Miz1, IRF1, and TBP (Massimi, Pim et al. 1996; Massimi, Pim et al. 1997; Park, Kim et al. 2000; Maldonado, Cabrejos et al. 2002; Habig, Smola et al. 2006; McLaughlin-Drubin, Huh et al. 2008; Morandell, Kaiser et al. 2012). E7 can also induce the expression of transcription factors such as B-Myb and c-Fos (Lam, Morris et al. 1994; Morosov, Phelps et al. 1994; Pang, Toh et al. 2014), and inhibit the expression of transcription factors such as STAT1 and IRF1 (Hong, Mehta et al. 2011; Zhou, Chen et al. 2013).

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