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HPV16 E6 confers p53-dependent and p53-independent phenotypes in the epidermis of mice deficient for E6AP

Department of Cancer Biology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Oncogene (Impact Factor: 8.56). 06/2007; 26(23):3321-8. DOI: 10.1038/sj.onc.1210130
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ABSTRACT High-risk human papillomaviruses are the causative agents of cervical and other anogenital cancers. In these cancers, two viral oncogenes, E6 and E7, are expressed. E6 is best known for its ability to inactivate the tumor suppressor p53, which is thought to arise through ubiquitin-mediated degradation of p53 and involve a ternary complex between E6, p53 and the E3 ligase, E6AP. In mice transgenic for wild-type HPV16 E6, its expression leads to epithelial hyperplasia and an abrogation of normal cellular responses to DNA damage. Whereas only the latter phenotype is dependent upon E6's inactivation of p53, both are reduced in transgenic mice expressing an E6 mutant severely reduced in its binding to E6AP and other cellular proteins that bind E6 through a shared alpha-helix motif. Here, we investigated whether E6AP is required for the induction of the above phenotypes through the use of both E6AP-mutant and E6AP-null mice. E6, in the absence of E6AP retains an ability to induce epithelial hyperplasia, abrogate DNA damage responses and inhibit the induction of p53 protein following exposure to ionizing radiation. We conclude that E6 is able to induce both p53-dependent and p53-independent phenotypes through E6AP-independent pathways in the mouse.

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    • "Among these targets are proteins containing multiple PDZ domains that bind to the C-terminus of E6, which include the tumour suppressor human discs large (hDlg) (Kiyono et al., 1997) and the MAGI family of proteins (Glaunsinger et al., 2000; Thomas et al., 2002), the pro-apoptotic protein Bak (Thomas and Banks, 1998) and c-Myc (Gross-Mesilaty et al., 1998). Recent studies suggest that additional E6 mediated p53 degradation pathways might exist that are independent of E6AP ligase activity (Camus et al., 2007; Massimi et al., 2008; Nomine et al., 2006; Shai et al., 2007). In addition, putative mechanisms modulating E6-mediated degradation have been proposed, which include proteasome-mediated degradation of both E6 (Stewart et al., 2004) and E6AP (Kao et al., 2000), stabilization of E6 by E6AP (Tomaic et al., 2009), E6 interaction with the deubiquitinating enzyme USP15 (Vos et al., 2009) and inhibition of the E6/E6AP activity by the EDD ubiquitin ligase (Tomaic et al., 2011). "
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    ABSTRACT: The viral oncoprotein E6 is an essential factor for cervical cancers induced by "high-risk" mucosal HPV. Among other oncogenic activities, E6 recruits the ubiquitin ligase E6AP to promote the ubiquitination and subsequent proteasomal degradation of p53. E6 is prone to self-association, which long precluded its structural analysis. Here we found that E6 specifically dimerizes through its N-terminal domain and that disruption of the dimer interface strongly increases E6 solubility. This allowed us to raise structural data covering the entire HPV16 E6 protein, including the high-resolution NMR structures of the two zinc-binding domains of E6 and a robust data-driven model structure of the N-terminal domain homodimer. Interestingly, homodimer interface mutations that disrupt E6 self-association also inactivate E6-mediated p53 degradation. These data suggest that E6 needs to self-associate via its N-terminal domain to promote the polyubiquitination of p53 by E6AP.
    Structure 04/2012; 20(4):604-17. DOI:10.1016/j.str.2012.02.001 · 6.79 Impact Factor
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    • "HR-HPV E6 is also able to interact with members of the PDZ family of proteins, promoting its proteasome-mediated degradation, an activity that seems to be required for induction of cervical cancer (Shai et al., 2007). HR-HPV E6 PDZ binding can mediate suprabasal cell proliferation and this is thought to occur by uncoupling the cell proliferation and polarity control that exist in a differentiated epithelium (Sterlinko et al., 2004). "
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    • "HPV-16 E6 can interact with dozens of intracellular proteins, but its interference with the tumor suppressive role of p53 is by far its best-studied activity. E6 and the intracellular ubiquitin ligase E6-associated protein (E6-AP) can bind to p53 in a ternary complex and induce its proteasomal degradation (Huibregtse et al. 1991; Scheffner et al. 1993; Scheffner et al. 1990; Werness et al. 1990); however, whether this is the only mechanism by which E6 can cause the degradation of p53 currently is unclear (Massimi et al. 2008; Shai et al. 2007b). E6-AP binds to E6 using a conserved α-helical motif (Chen et al. 1998; Elston et al. 1998) which is shared by a variety of other binding partners of E6, including E6-binding protein (E6-BP) (Chen et al. 1995; Elston et al. 1998), paxillin (Chen et al. 1998; Vande Pol et al. 1998), tuberin (Elston et al. 1998; Lu et al. 2004), and interferon regulatory factor-3 (IRF-3) (Ronco et al. 1998). "
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    ABSTRACT: High-risk human papillomaviruses (HPVs) contribute to cervical and other anogenital cancers, and they are also linked etiologically to a subset of head and neck squamous cell carcinomas (HNSCC). We previously established a model for HPV-associated HNSCC in which we treated transgenic mice expressing the papillomaviral oncoproteins with the chemical carcinogen 4-nitroquinoline-1-oxide (4-NQO). We found that the HPV-16 E7 oncoprotein was highly potent in causing HNSCC, and its dominance masked any potential oncogenic contribution of E6, a second papillomaviral oncoprotein commonly expressed in human cancers. In the current study, we shortened the duration of treatment with 4-NQO to reduce the incidence of cancers and discovered a striking synergy between E6 and E7 in causing HNSCC. Comparing the oncogenic properties of wild-type versus mutant E6 genes in this model for HNSCC uncovered a role for some but not other cellular targets of E6 previously shown to contribute to cervical cancer.
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