Degradation of HPV20E6 by p53: ΔNp63α and mutant p53R248W protect the wild type p53 mediated caspase‐degradation

Abstract

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 DNp63a, 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.

Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas

“…A similar inverse correlation has been reported in oropharyngeal squamous cell carcinomas [78] and head and neck carcinomas [79], [80], [81] in which HPV positive tumors were associated with wild type TP53 and HPV negative tumors had a higher frequency of Tp53 mutations. In contrast, recent in vitro studies have shown that expression of wt Tp53 can inhibit HPV replication by blocking the expression, and promoting the degradation of HPV20 E6 [82], while the common hot spot mutation R248W confers a protective effect on the HPV20 E6 protein to promote viral replication [83].…”

Detection of mucosal and cutaneous human papillomaviruses in oesophagitis, squamous cell carcinoma and adenocarcinoma of the oesophagus

“…35 Several in vitro models have shown that E6 proteins from diverse cutaneous HPV types influence both growth and differentiation of primary human keratinocytes in organotypic raft cultures 52 and inhibit apoptosis in response to UV irradiation. [53][54][55] Furthermore, E6 genes of HPV types 12, 14, 15, 24 36, and 49 have been shown to have a significant transforming potential in vitro in cooperation with activated ras. 56 All these results provide molecular support for an indirect role of these viruses (i.e.…”

Mapping of Betapapillomavirus Human Papillomavirus 5 Transcription and Characterization of Viral-Genome Replication Function

“…The exact functions of the betapapillomavirus E6 and E7 ORF products remain poorly understood. Compared with high-risk mucosal HPV types, E6 expression among cutaneous HPVs is differentially regulated through wt p53, and cutaneous HPV E6 proteins do not induce the proteasome-mediated degradation of p53 or PDZ domain proteins (48,49). However, E6 gene expression from several cutaneous HPV types protects keratinocytes from UV-B-induced apoptosis (50,51) by mediating the degradation or reduction of the levels of the proapoptotic Bak protein, thereby preventing the release of proapoptotic factors from the mitochondria (52,53).…”