B cell lines latently infected with EBV are immortal and can proliferate indefinitely. EBNA2 is one of the latency proteins that is essential for immortalization. The long-term goal of this project is to understand how EBNA2 contributes to the reprogramming of B cell gene expression that follows EBV infection. EBNA2 is a transcriptional transactivator that interacts with the cellular DNA binding protein CBF1. Recently, a linkage has been made between the EBNA2-CBF1 interaction and Notch signal transduction. It is proposed to build on this observation to further elucidate the downstream signaling events that initiate the immortalization process.
The Specific Aims are: [1] To further characterize EBNA2 transactivation mechanisms by (i) using mutagenesis to define the EBNA2 interaction interface on CBF1 and (ii) examining the functional consequences of EBNA2 interaction with cell transcription factors. [2] To determine the contribution of the new CST-1 latency protein to in vivo latency and EBV-associated tumorigenesis by (i) characterizing CST-1 mRNA and protein expression in peripheral blood lymphocytes and EBV-associated tumors and (ii) testing the ability of CST-1 to block Notch signaling in a model differentiation system. [3] To characterize signaling events downstream of CBF1 by determining the role in transcriptional regulation of two novel cellular proteins that are linked to CBF1 and [4] To initiate structural studies of the domains involved in CBF1 interaction with Notch and EBNA2.
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