Epstein-Barr virus (EBV) is associated with a variety of human malignancies (62). In settings such as posttransplant lymphoproliferative disease, where the full latency III program is expressed, EBV nuclear-associated protein 2 (EBNA2) and LMP1 make critical contributions (10, 41). The Cp promoter that drives EBNA2 expression along with that of EBNA-LP and EBNA3A, -3B, and -3C is regulated by EBNA2 (39, 52, 72), as are the promoters for LMP1 and LMP2A (40,49,85,91). EBNA2 also contributes to dysregulated cellular growth proliferation and provides a cell survival function. EBNA2 is a transcriptional activator that targets responsive promoters through interactions with the cell DNA-binding proteins Pu.1 and CBF1 (RBPJ-) (20, 26, 31,48,83,92).In targeting CBF1, EBNA2 mimics activated Notch, NotchIC, and thus EBNA2 can modify cellular gene transcription in a manner that resembles constitutively activated Notch signaling (24, 32, 37,71,90). NotchIC has a separate antiapoptotic activity mediated through targeting of the immediateearly response factor Nur77 (38), and this activity is also demonstrated by EBNA2 (50).LMP1 functions as a constitutively active tumor necrosis factor receptor and mimics aspects of CD40 signaling (15, 23,58,81). The cytoplasmic carboxy terminus of LMP1 contains two effector domains, CTAR1 and CTAR2, that interact with tumor necrosis factor receptor-associated factors and with tumor necrosis factor receptor-associated death domain and receptor interacting protein, respectively, to activate NF-B, p38 mitogen-activated protein kinase, and JNK pathways (12,14, 16, 22, 33, 35, 36,43,56,73). As a downstream consequence of these pathways, LMP1 provides a cell survival function through upregulation of antiapoptotic proteins such as Bcl-2, Mcl-1, Bfl-1, and A20 (13, 18, 25,47,86) and alters cell growth through induction of epidermal growth factor receptor and cytokines such as interleukin-6 (IL-6) (16, 17, 28,55). Another