Mdm2, an oncoprotein that regulates the tumor suppressor p53, and Myc, an oncoprotein that paradoxically drives both cell cycle progression and apoptosis, are overexpressed in many human malignancies. We have demonstrated in vivo that Mdm2 overexpression was frequently selected for during Myc-induced B cell lymphoma development in E?-myc transgenic mice, a murine model of human non-Hodgkin's lymphoma where Myc is overexpressed specifically in B cells. Surprisingly, Mdm2 overexpression frequently occurred in lymphomas that had inactivated p53 or p19ARF, a regulator of Mdm2. These observations suggest that Mdm2 plays a role in lymphomagenesis, and that Mdm2 may function independent of both tumor suppressors p53 and ARF during lymphoma development. We will test these hypotheses with in vivo approaches utilizing mouse tumor models and in vitro primary pre-B cell and tumor cell analyses. Experiments in Aim #1 will determine, in a genetic fashion, the impact of Mdm2 overexpression on B cell development and transformation and the extent to which Mdm2 synergizes with Myc during lymphoma development. Experiments in Aim #2 will evaluate the influence Mdm2 expression has on Myc-induced apoptosis and whether Mdm2 is required for Myc-induced lymphomagenesis. Experiments in Aim #3 will identify and characterize novel targets of Mdm2 and p53/ARF-independent pathways that mediate Mdm2's oncogenic properties. Together these studies will elucidate the role(s) Mdm2 has in lymphoma development and provide much needed insight on the mechanisms involved in B cell transformation. Results from these investigations should ultimately lead to improved intervention strategies for the treatment of human non-Hodgkin's lymphoma. ? ?
