Lymphoid Transformation with Human Herpesvirus 8 K1

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DESCRIPTION (provided by applicant): In this K22 award application, the PI describes plans for career development through a comprehensive research plan to define the role of HHV-8 K1 in lymphocytes and lymphoma. The PI has generated data showing that the K1 gene codes for a transmembrane protein with an immunoreceptor tyrosine-based activation motif (ITAM). K1 stimulates NF-kappaB activity and K1 expression in transgenic mice induces lymphoma development. Lymphoma cells expressing K1 became resistant to apoptosis that is induced by fas antibody. Equipped with the reagents and models described, the PI will be able to complete the proposed studies showing the role of K1 in lymphocyte signaling and possible transformation. The hypothesis to be tested is that K1 expression in lymphocytes and lymphoma cells stimulates NF-kappaB signaling and other pathways, leading to the transformation of lymphocytes and development of lymphoma. Specific Aim 1. To establish whether K1 expression is associated with the development of lymphoma. New lines of transgenic mice will be developed and the resulting lymphomas characterized. Specific Aim 2. To delineate the signaling pathway of K1 in lymphoma cells and lymphocytes. Using dominant negative constructs and specific active blocking reagents that target NF-kappaB, NFAT, or AP-1, the pattern of K1 signaling will be determined. ITAM deleted K1 and other constructs will be used to identify K1's signaling pathway. Specific Aim 3. To determine whether K1 suppresses apoptosis. Early mediators of fas-dependent apoptosis will be characterized through monitoring of caspase activation. K1 can induce lymphocyte signaling that may constitute the early steps leading to lymphocyte transformation. By analyzing K1 signaling in lymphocytes and its long-term expression in transgenic mice, we will determine K1's role in mediating cell signaling and lymphoma development. By carrying out the plans in this application, the PI will show how a viral gene participates in inducing lymphoma and offer insights into therapy.