While its importance in transformation is evident, it should be noted that MT also plays a significant role in PyV infection. As inhibitors of PI3K now enter the clinic, there is real hope that this basic research will have important practical outcomes. The importance of tyrosine phosphorylation and PI3K were first appreciated by studying MT. In vivo tumorigenesis is important because signal transduction hypotheses developed in the laboratory can be tested in animals. Expressed from a transgene, MT causes tumors in a variety of tissues. It is also critical for tumorigenesis after viral infection. As we discuss in detail below, MT is necessary, and in many cases sufficient, for transformation in tissue culture. T-antigen coding sequences are in different colors to emphasize reading frame differences.Īlthough LT and ST also have independent abilities to regulate cell growth and survival, MT is the most important PyV transforming protein. Replication and transcription are controlled by the enhancer (ENH) and the origin of viral DNA replication (ORI). Late transcription of the capsid proteins (VP1, VP2, and VP3) is counterclockwise. Early transcription of the T antigens proceeds in a clockwise direction.

The genomic arrangement has sometimes made it hard to decipher individual roles of each protein in virus experiments. All three T antigens are involved in both virus replication and in cell transformation. Other polyomaviruses (for example, simian virus 40 and the human viruses BK and JC) lack it. PyV and hamster polyomavirus ( 65, 80, 122) are the only two family members that have MT. This arrangement of gene products is, depending on the point of view, either a quirk or a stroke of evolutionary genius. LT, MT, and ST antigens each have a unique C-terminal sequence of 706, 230, and 4 amino acids, respectively. MT and ST share an additional 112 amino acids. The pattern of splicing is such that all T antigens share a common 79-amino-acid J domain connecting the T antigens to molecular chaperone ( 27, 157, 238, 265, 278, 281, 283). A fourth spliced product of unknown function, tiny T ( 238), has been observed in some situations. These viral oncoproteins are produced by differential splicing of the viral early region ( 296) (Fig. The three early proteins studied for their contributions to neoplastic transformation are named large, middle, and small tumor antigen (LT, MT, and ST, respectively), because they were discovered using antibodies from tumor-bearing animals. PyV can cause a wide variety of tumors in different types of cells ( 78, 96, 105). It is a testament to the importance of these issues that they have already generated over 100,000 papers. Since the discovery of murine polyomavirus (PyV) in the 1950s ( 123, 279), this virus family has called attention to, among other things, tyrosine phosphorylation, phosphoinositide 3-kinase (PI3K), and p53. Insights into basic mechanisms that regulate cell growth and the impact of their deregulation have emerged from transformation and tumorigenesis studies. Much of our understanding of eukaryotic transcription and replication mechanisms has come from studies of their lytic cycles. Polyomaviruses have proven to be invaluable models.

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