Abstract:
:Cervical cancer develops through the combined activities of the human papillomavirus (HPV) E6 and E7 oncoproteins. A defining characteristic of E6 oncoproteins derived from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at the extreme carboxy terminus of the protein which is absent from E6 proteins derived from the so-called low-risk HPV types. Within this PBM is also a protein kinase A (PKA) phospho-acceptor site, which is thought to negatively regulate the association of E6 with its PDZ domain-containing substrates. We can now show that phosphorylation of E6 by PKA and/or AKT confers the ability to interact with 14-3-3ζ. The interaction is direct and specific for the high-risk HPV E6 oncoproteins, although there are significant differences in the efficiencies with which HPV-16, HPV-18, and HPV-31 E6 oncoproteins can associate with 14-3-3ζ; this correlates directly with their respective susceptibilities to phosphorylation by PKA and/or AKT. We demonstrate here that the interaction between E6 and 14-3-3ζ also requires integrity of the E6 PBM, and downregulation of 14-3-3ζ results in a marked reduction in the levels of HPV-18 E6 expression in HeLa cells. Using phospho-specific anti-E6 antibodies, we also demonstrate significant levels of E6 phosphorylation in vivo. These studies redefine the potential relevance of the E6 PBM in the development of cervical cancer, suggesting that interaction with 14-3-3ζ, as well as the more well-established interactions with PDZ domain-containing substrates, is likely to be responsible for the biological activities attributed to this region of the high-risk HPV E6 oncoproteins.
journal_name
J Viroljournal_title
Journal of virologyauthors
Boon SS,Banks Ldoi
10.1128/JVI.02074-12subject
Has Abstractpub_date
2013-02-01 00:00:00pages
1586-95issue
3eissn
0022-538Xissn
1098-5514pii
JVI.02074-12journal_volume
87pub_type
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更新日期:2014-08-01 00:00:00
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pub_type: 杂志文章
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更新日期:1988-09-01 00:00:00
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更新日期:1974-10-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/JVI.21.1.1-6.1977
更新日期:1977-01-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.10.6557-6562.1996
更新日期:1996-10-01 00:00:00
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pub_type: 杂志文章
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更新日期:1998-05-01 00:00:00
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
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更新日期:1993-07-01 00:00:00
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pub_type: 杂志文章
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更新日期:1999-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2007-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:1998-09-01 00:00:00
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pub_type: 杂志文章
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更新日期:2014-10-01 00:00:00