Large T antigen is the major transforming protein of the primate viruses. Its expression is both necessary and sufficient for the oncogenic transformation of most cell types (Martin and Chou, 1975; Brockman, 1978; Tegtmeyer, 1975; Brugge and Butel, 1975). The TAg of PyV differs from its primate cousins in that it is not required for maintenance of the transformed state: that function falls upon middle T antigen (Di Mayorca et al., 1969; Eckhart, 1969; Fried, 1965; Basilico et al., 1980; Lania et al., 1980). Small t antigen is required for transformation under certain conditions, working through its interaction with PP2A. The ability of small t to bind PP2A correlates with its ability to induce cell growth (Mungre et al., 1994).
The capacity of TAg to transform cells maps to at least three domains of the molecule: the pRb binding and J domains discussed above and a more carboxy-terminal domain that allows TAg to bind to the tumor suppressor protein p53 (for review, see Pipas, 1992). It is worth noting here that p53 was originally identified through its ability to coprecipitate with TAg (Lane and Crawford, 1979; McCormick and Harlow, 1980; Linzer and Levine, 1979). Our current understanding of the mechanism of transformation is as follows. TAg expression leads to the induction of S phase through the pRb-binding and J domain functions described above. The cell responds to this abnormal signal to divide by turning on a p53 response, which would normally lead to cell cycle arrest or apoptosis. TAg overcomes this roadblock, however, by binding to p53 and inhibiting its function. Thus, the cell is induced to proliferate, and p53-mediated check point control is abrogated. The purpose of the interaction with pRb and p53 pathways during lytic infection is therefore to push the cell into a maximal environment for the support of viral DNA replication and to keep it alive as long as possible to optimize viral yields before the cell is killed. Oncogenic transformation occurs when there is a block to productive infection, but continued expression of TAg. This leads to cell proliferation without killing of the cell, ultimately resulting in tumor formation in the nonpermissive host due to the restrictive nature of the virus-cell interaction relating to DNA replication. One can also obtain oncogenic transformation in a permissive host if viral replication is blocked by other means, such as mutations in the origin of replication (Gluzman, 1981). Finally, one must keep in mind that TAg itself can induce DNA damage, making its inactivation of p53 doubly dangerous to the cell (Theile and Grabowski, 1990; Lazutka et al., 1996; Tognon et al., 1996; Trabanelli et al., 1998; Ray et al., 1990).
In addition to the large and small T antigens, the third PyV T antigen, middle T antigen, is required for transformation by the mouse virus. While PyV large T antigen does bind to and deregulate pRb family members, working through the same functional domains as the primate TAg (Larose et al., 1991; Freund et al., 1992a; Sheng et al., 1997), it does not bind to p53. PyV small t antigen does affect PP2A function and appears to serve an identical function to SV40 small t antigen (Pallas et al., 1988). Middle T antigen acts through a distinctly different mechanism than the other two oncoproteins. Its membrane-bound location puts it in a position to bind to and activate Src family kinases, thereby signaling the cell to grow and divide via a kinase cascade pathway (Kaplan et al., 1989).
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