CD40-INDUCED GROWTH-INHIBITION IN EPITHELIAL-CELLS IS MIMICKED BY EPSTEIN-BARR VIRUS-ENCODED LMP1 - INVOLVEMENT OF TRAF3 AS A COMMON MEDIATOR

CD40, a member of the tumour necrosis factor receptor family, is expre ssed on the surface of B lymphocytes where its ligation provides a pot ent survival signal. CD40 is also expressed in basal epithelial cells and in a number of different carcinomas where its function remains unk nown. We observed that contrary to the studies in normal B cells, CD40 Ligation in carcinoma cell lines and in normal primary epithelial cel ls resulted in growth inhibition and enhanced susceptibility to apopto sis induced by anti-neoplastic drugs, TNF-alpha, Fas and ceramide. Thi s effect was also observed in CD40-transfected Rat-1 fibroblasts. The expression of Bcl-2 did not affect growth inhibition induced by CD40 l igation in epithelial cells but the Epstein - Barr Virus-encoded laten t membrane protein 1 (LMP1) blocked the effect. Whilst transient expre ssion of LMP-1 resulted in the inhibition of epithelial cell growth, t his effect was not observed with a LMP1 mutant lacking the binding dom ain for TRAF3, a protein which may mediate signal transduction by inte racting with the cytoplasmic domains of both CD40 and LMP1. Transient expression of TRAF3 also inhibited epithelial cell growth, whilst expr ession of a dominant-negative TRAF3 partially blocked the inhibitory e ffect of CD40 ligation and of transient LMP1 expression. These results suggest that CD40 regulates epithelial cell growth in a manner mimick ed by LMP1 and implicate TRAF3 as a common mediator in the transductio n of the growth inhibitory signals generated via the CD40 and LMP1 pat hways.