Degradation of HPV20E6 by p53: Delta Np63 alpha and mutant p53R248W protect the wild type p53 mediated caspase-degradation.
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 Delta Np63 alpha, 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.
Fei
Jian-Wei
JW
Division for Characterization of Tumorviruses, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
de Villiers
Ethel-Michele
EM
D017209:Apoptosis; D001120:Arginine; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000821:virology*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000821:virology*; D013058:Mass Spectrometry; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014364:Tryptophan; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D004268:DNA-Binding Proteins; C529089:E6 protein, human papillomavirus type 20; D009856:Oncogene Proteins, Viral; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D014746:Vimentin; D014364:Tryptophan; D001120:Arginine; D005982:Glutathione Transferase; D053148:Caspase 3