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

Baylor University, Waco, Texas, United States
Oncogene (Impact Factor: 8.46). 06/2007; 26(23):3321-8. DOI: 10.1038/sj.onc.1210130
Source: PubMed


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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    • "E6AP is also important for E6 mediated degradation of other cellular partners such as hScribble, a PDZ domain partner [7], hMCM7 [8], E6TP1 [9], and Myc [10] which is involved in activation of TERT [11]. However, E6 also can inactivate p53 independently of E6AP [12], [13]. Besides E6AP, HPV16 E6 interacts with several other cellular proteins, including ATF3 [14], E6BP [15], hDLG [16], IRF-3 [17], Bak [18], and hTERT [19]. "
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    ABSTRACT: High risk subtype HPV16 early oncoprotein E6 contributes host cell immortalization and transformation through interacting with a number of cellular factors. ING4 is one member of the inhibitor of growth (ING) family of type II tumor suppressors and it has been shown to be involved in regulating p53 function. However, the effect and mechanism of HPV16 E6 on ING4 function remain elusive. In this study, we report HPV16 E6 combines with ING4 in vivo and in vitro. The ING4 induced p53 acetylation and its combining with p53 were attenuated by HPV16 E6 independent of p53 degradation. The enhancing function of ING4 on p53 mediated apoptosis was diminished when HPV16 E6 existed. These findings reveal that ING4 may be a common target of oncogenic viruses for driving host cell carcinogenesis.
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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.
    Full-text · Article · Apr 2012 · Structure
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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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