Cellular transformation by Simian Virus 40 and Murine Polyoma Virus T antigens

Abstract

Simian Virus 40 (SV40) and Mouse Polyoma Virus (PY) are small DNA tumor viruses that have been used extensively to study cellular transformation. The SV40 early region encodes three tumor antigens, Large T (LT), small T (ST) and 17KT that contribute to cellular transformation. While PY also encodes LT and ST, the unique Middle T (MT) generates most of the transforming activity. SV40 LT mediated transformation requires binding to the tumor suppressor proteins Rb and p53 in the nucleus and ST binding to the protein phosphatase PP2A in the cytoplasm. SV40 LT also binds to several additional cellular proteins including p300, CBP, Cul7, IRS1, Bub1, Nbs1 and Fbw7 that contribute to viral transformation. PY MT transformation is dependent binding to PP2A and the Src family protein tyrosine kinases (PTK) and assembly of a signaling complex on cell membranes that leads to transformation in a manner similar to Her2/neu. Phosphorylation of MT tyrosine residues activates key signaling molecules including Shc/Grb2, PI3K and PLCγ1. The unique contributions of SV40 LT and ST and PY MT to cellular transformation have provided significant insights into our understanding of tumor suppressors, oncogenes and the process of oncogenesis.

Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes

“…The main transforming activity of MPyV is encoded by the middle T antigen (MT), which splices the first exon corresponding to ST to the overprinting frame in exon 2. Studies of MT in MPyV have led to discoveries of phosphotyrosine kinases (PTK) and phosphoinositide 3-kinase (PI3K) signaling (9,22). Although ALTO does not appear to be essential for viral genome replication, we find that it is mutated in many cancer tissues and that elucidation of its function may uncover new roles for ALTO in MCPyV manipulation of human cell signaling and perhaps in cancer development.…”

“…Polyomaviruses leverage alternative splicing of the early region (ER) of the genome to generate protein diversity, including the large and small T antigens (LT and ST, respectively) and the middle T antigen (MT) of murine polyomavirus (MPyV), which is generated by a novel splicing event and overprinting of the second exon of LT. Some polyomaviruses can drive tumorigenicity, and gene products from the ER, especially SV40 LT and MPyV MT, have been extraordinarily useful models to study the viral and host processes required for cellular transformation (9)(10)(11). More recently, a new oncogenic polyomavirus, Merkel cell polyomavirus (MCPyV), was discovered in Merkel cell carcinoma (MCC), a rare but aggressive form of skin cancer, providing the first established case of a human cancer stemming from a polyomavirus infection (12,13).…”

Lack of epithelial-to-mesenchymal transition induction in two bronchial epithelial cell lines after alpha and gamma irradiation

“…The BEAS-2B line was created by adenovirus-12-SV40 hybrid viral transformation and the cells have been shown to express SV40 T-antigens (Reddel et al, 1993). The SV40 large T-antigen has been linked to cell immortalisation by its binding to tumour suppressor proteins Rb and p53 which may inhibit important regulatory pathways thus making the cells susceptible to tumourigenesis (Cheng et al, 2009). Part of that process is that the cells may become more prone to TGF-β-induced EMT (Sato et al, 2013).…”

Phosphorylation of Merkel Cell Polyomavirus Large Tumor Antigen at Serine 816 by ATM Kinase Induces Apoptosis in Host Cells

“…The T antigens from several polyomaviruses have oncogenic activity. Notably, the SV40 large and small T antigens can transform a variety of rodent and human cells (17,18). In addition, LT from SV40, as well as the human JC and BK polyomaviruses, can bind to pRb and p53 tumor suppressor proteins (19 -22).…”