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Degradation of HPV20E6 by p53: ΔNp63α and mutant p53R248W protect the wild type p53 mediated caspase‐degradation
Author(s) -
Fei JianWei,
de Villiers EthelMichele
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23506
Subject(s) - pdz domain , ubiquitin ligase , microbiology and biotechnology , ubiquitin , biology , deubiquitinating enzyme , mutant , cancer research , chemistry , genetics , gene
The E6 and E7 proteins of human papillomaviruses (HPV) play a crucial role in the pathogenesis of malignant tumors. E6 protein of high‐risk mucosal papillomaviruses targets a number of proteins for proteosomal degradation through complex formation with ubiquitin ligase E6AP. These proteins include, amongst others, p53, paxillin and PDZ‐domain proteins e.g . Dlg and MAGUK. The mechanism by which the E6 protein of cutaneous HPV types interacts with cellular proteins to induce either benign or malignant cutaneous lesions, has not been elucidated, although extensive ultraviolet exposure and mutated p53 ( hot‐spot mutations) are known to be associated with non‐melanoma skin cancer. We demonstrate two mechanisms in which HPV20E6 may be involved in the infected cell. One pathway is the wtp53 mediated degradation of HPV20E6 through caspase‐3. Mutated p53R248W and ΔNp63α, as well as other unknown proteins involved in proteosome‐dependent degradation, convey a protective effect on HPV20E6 under these conditions. This unveils a remarkable opposite regulation to the well‐known mechanism of E6‐E6AP mediated degradation of p53 for mucosal HPV types. In a second interaction, ectopically expressed HPV20E6 induces cleavage of procaspase‐3 to active caspase‐3. We demonstrate, in addition, in vivo binding of HPV20E6 to the intermediate filament vimentin. © 2008 Wiley‐Liss, Inc.