Dr. DeCaprio has obtained evidence that two transforming domains of SV40 large T antigen (Ag) specifically and functionally target the retinoblastoma (pRB)-related proteins, p130 and p107. In normal cells, pRB, p107 and p130 undergo cell cycle-dependent phosphorylation. However, in cells expressing T Ag, there are greatly reduced levels of phosphorylated p130 and p107 with apparently normal levels of phosphorylated pRB. The LXCXE domain of T Ag (residues 103 to 107) is required for binding to the pRB-related proteins and the N-terminus (residues 1 to 82) is necessary to reduce the cellular levels of phosphorylated p107 and p130. They have recent evidence that the requirement for an intact N-terminus of T Ag can be met by substitution with the J domain from two human DNAJ homologues. These observations suggest that, in addition to the functional neutralization of the pRB growth suppression function, transformation by T Ag includes a specific effect on p130 and p107.
The specific aims of this application are designed to determine if the pRB-related proteins, p130 and p107, are specifically targeted by T Ag during transformation. In this context, they will examine the ability of T Ag to transform mouse embryo fibroblasts (MEFs) derived from knockout strains deleted for p107 and p130. They will examine whether the ability of T Ag to transform these cells is dependent on both the LXCXE and N-terminal domains. They propose to determine what elements of the N-terminus of T Ag contribute to transformation and a decrease in levels of phosphorylated p130 and p107. They will compare the ability of other papova viral T Ags and various DNAJ-T Ag chimeras to reduce levels of phosphorylated p130 and determine whether this effect is specific for SV40 or is shared with other papova T Ags and DNAJ homologues. In addition, they will explore the molecular mechanism of T Ag s ability to reduce the cellular levels of phosphorylated p130 and p107. In the course of the work, they will attempt to better understand the normal transformation suppression functions of the pRB-related proteins, p130 and p107.
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