SV40 large T antigen (T Ag) is capable of transforming a wide variety of cell types. T Ag transformation is dependent in part upon its interaction with several tumor suppressors including p53, Rb and the Rb-related proteins p107 and p130. T Ag's LxCxE motif binds directly to pRb family members. The N-terminal DnaJ homology domain of T Ag cooperates with the LxCxE motif to disrupt the interaction between pRb and E2F transcription factors. A bipartite C-terminal domain of T Ag binds to p53 and also contributes to binding to the transcriptional co-activators p300 and CBP (CREB binding protein. While mutations of p300 and CBP have been observed in human cancers, it is not known if T Ag binding to CBP and p300 contributes to the transformed phenotype. Furthermore, little information is available that distinguishes the normal or oncogenic activities of the p300 and CBP. Preliminary data from this laboratory has demonstrated that T Ag is specifically acetylated in a CBP dependent manner. In addition, loss of p300 activity and not CBP contributes to T Ag's ability to form tumors. These observations support the hypothesis that interaction between T Ag and p300/CBP contributes to the T Ag transforming mechanism. We propose that T Ag selectively inactivates p300 while preserving at least some CBP function. This application seeks to test this hypothesis by the following specific aims: 1. Define the role of p53 in SV40 T Ag binding to p300 and CBP. We will determine if T Ag binding to p300/CBP is direct or mediated through p53. We will define the domains of T Ag, p53, and p300/CBP required for this interaction. We will also determine whether specific post-translational modification of p53 and T Ag affects the interaction between T Ag and p300/CBP. 2. Determine the effect of T Ag on p300 and CBP function. p300 and CBP are transcriptional co-activators capable of binding to many transcription factors. p300 and CBP have intrinsic histone acetyl transferase (HAT) activity. We will determine whether T Ag binding to p300/CBP affects the ability of p300/CBP to bind to sequence-specific transcription factors, affects their HAT activity, and perturbs their role as transcriptional co-activators. 3. Determine the contribution of p300 and CBP to T Ag transformation. We will determine whether T Ag interaction with p300 and CBP is required for cellular transformation in MEFs derived from p300 and CBP knockout strains. Using a variety of genetic, biochemical, and molecular approaches, we will focus on determining the specific contribution of p300 and CBP to T Ag transformation.
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