Abstract
E6 from high risk human papillomaviruses (HR HPVs) promotes ubiquitination and degradation of p53 tumour suppressor by mediating its binding to ubiquitin ligase E6AP in a ternary complex, contributing to cell transformation in cervical cancer. We have previously shown that Felis catus papillomavirus type −2 (FcaPV-2) E6 is expressed in feline squamous cell carcinoma (SCC) and displays the ability to bind p53 and decrease its protein levels in transfected CRFK cells. However, the mechanism of p53 downregulation has not yet been characterized. Here we show that FcaPV-2 E6 bound to E6AP, which in turn was bound by p53 exclusively in cells expressing the viral oncoprotein (CRFKE6). Furthermore, p53 was highly poly-ubiquitinated and underwent accumulation upon E6AP gene knockdown in CRFKE6. Half-life experiments and proteasome inhibition treatments indicated that down-regulation of p53 protein in CRFKE6 was due to accelerated proteasomal degradation. E6AP/p53 binding was also demonstrated in two feline SCC cell lines expressing FcaPV-2 E6, where p53 protein levels and poly-ubiquitination degree were proportional to E6 mRNA levels. The data obtained in both artificial and spontaneous in vitro models suggest that FcaPV-2 E6 degrades p53 through a molecular mechanism similar to HR HPVs, possibly contributing to the development of feline SCC.
Highlights
Alpha high-risk (HR) human PV types-16/-18 (HPV-16/-18) are clearly associated with cervical cancer and the mechanism by which their E6 down-regulate p53 has been extensively investigated and well characterized
The E6 from mucosal high risk human papillomaviruses (HR HPVs) promotes the assembly of a ternary complex with E6AP and p53, causing enhanced ubiquitination and proteasomal degradation of the latter[2]
The co-IP of E6AP with Felis catus papillomavirus type −2 (FcaPV-2) E6 confirmed the ability of the viral oncoprotein to recruit the ubiquitin ligase and this, along with E6AP co-IP with p53 exclusively in CRFKE6, suggests the occurrence of the triple binding
Summary
Alpha high-risk (HR) human PV types-16/-18 (HPV-16/-18) are clearly associated with cervical cancer and the mechanism by which their E6 down-regulate p53 has been extensively investigated and well characterized. It is widely recognized that HR HPVs, HPV-16, are involved in the pathogenesis of a sub-group of oropharyngeal squamous cell carcinoma (SCC) by exerting the same transforming mechanisms[4] This type of oral cancer forms a distinct category of head and neck SCC (HNSCC), with different markers and prognosis with respect to that associated with other risk factors such as tobacco smoke and alcohol consumption[4]. Similar molecular studies were extended to cell lines derived from spontaneous feline oral SCC, in order to describe their molecular scenario and hypothesize whether it might take place in an in vitro model of naturally occurring cancer
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