TRADD Domain of Epstein-Barr Virus Transforming Protein LMP1 Is Essential for Inducing Immortalization and Suppressing Senescence of Primary Rodent Fibroblasts

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Abstract
Mutation analysis of latent membrane protein 1 (LMP1) in Epstein-Barr virus (EBV)-induced B-cell immortalization revealed two transformation effector sites, TES1 and TES2. TES2 mediates the interaction with tumor necrosis factor receptor-associated death domain protein (TRADD) and plays a key role in transactivating NF-κB and AP-1. Recombinant EBV containing LMP1 with TES2 deleted induces a limited proliferation of B cells. The present study shows that a mutant with an LMP1 site-specific mutation at TES2, LMP1 TRADD , initially stimulates cell growth and significantly extends the life span of MEF. However, it is not sufficient for the immortalization of MEF, and MEF-LMP1 TRADD cells eventually enter growth arrest. Further analysis reveals that although LMP1 TRADD promotes cell growth, it does not prevent the eventual onset of senescence and the expression of tumor suppressor p16 Ink4a .