Abstract
Approximately 15–20% of human cancer is related to infection, which renders them potentially preventable by antimicrobial or antiviral therapy. Human polyomaviruses (PyVs) are relevant in this regard, as illustrated by the involvement of Merkel cell polyomavirus (MCPyV) in the development of Merkel cell carcinoma. The polyomavirus Small and Large tumor antigen (ST and LT) have been extensively studied with respect to their role in oncogenesis. Recently it was shown that a number of human PyVs, including MCPyV and the trichodysplasia spinulosa polyomavirus (TSPyV), express additional T-antigens called Middle T (MT) and alternative T (ALT). ALT is encoded by ORF5, also known as the alternative T open reading frame (ALTO), which also encodes the second exon of MT, and overlaps out-of-frame with the second exon of LT. Previously, MT was considered unique for oncogenic rodent polyomaviruses, and ALT was still unknown. In this mini-review, we want to point out there are important reasons to explore the involvement of MT and ALT in human cellular transformation. First, just like their rodent equivalents, MT and ALT probably disrupt cellular pathways that control signaling and proliferation. Second, expression of the MT and ALT-encoding ORF5/ALTO characterizes a monophyletic polyomavirus clade that includes human and animal PyVs with known oncogenic potential. And third, ORF5/ALTO is subject to strong positive selection aimed specifically at a short linear motif within MT and ALT that overlaps completely with the RB-binding motif in LT. The latter suggests tight interplay between these T-antigens with possible consequences for cell transformation.
Highlights
An established causal relationship between a certain cancer and a particular infection provides ample opportunities to study oncogenesis in detail, and identify unique targets for cancer prevention and treatment
The polyomavirus Small and Large T-antigens (ST and LT) that resemble human papillomavirus (HPV) E6 and E7 in several ways, are the usual suspects when it comes to cellular transformation, as they are known to deregulate cellular pathways controlling the cell cycle, DNA repair, and apoptosis. The focus of this mini-review, will be on two other T-antigens, Middle T (MT) and Alternative T (ALT), both encoded by the Alternate T-antigen open reading frame (ALTO), known as ORF5, depending on the polyomavirus in which the open reading frame was recognized (Carter et al, 2013; van der Meijden et al, 2013b; Lauber et al, 2015)
ORF5/alternative T open reading frame (ALTO) is expressed by Merkel cell polyomavirus (MCPyV) (Carter et al, 2013) and by the trichodysplasia spinulosa polyomavirus (TSPyV) that causes dysplasia of human hair inner root sheath cells and follicular spine formation of the skin
Summary
An established causal relationship between a certain cancer and a particular infection provides ample opportunities to study oncogenesis in detail, and identify unique targets for cancer prevention and treatment. The focus of this mini-review, will be on two other T-antigens, Middle T (MT) and Alternative T (ALT), both encoded by the Alternate T-antigen open reading frame (ALTO), known as ORF5, depending on the polyomavirus in which the open reading frame was recognized (Carter et al, 2013; van der Meijden et al, 2013b; Lauber et al, 2015). ORF5/ALTO is expressed by MCPyV (Carter et al, 2013) and by the trichodysplasia spinulosa polyomavirus (TSPyV) that causes dysplasia of human hair inner root sheath cells and follicular spine formation of the skin (van der Meijden et al, 2010, 2015).
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