FUNGAL METABOLITE FR901228 INHIBITS C-MYC AND FAS LIGAND EXPRESSION

Activation of T lymphocytes often leads to cellular activation, produc tion of cytokines, entry into cell cycle, and expression of Fas (CD95) and Fas ligand (FasL), Although it is well established that the inter action of Fas and Fast results in apoptosis, mechanisms for regulated expression of Fas and Fast are unclear. Our previous work with antisen se oligodeoxynucleotides suggested that the protooncogene c-myc is obl igatory for activation-induced apoptosis, To study the relationship be tween myc and the Fas/FasL expression, we employed the antisense metho d and a newly identified fungal metabolite, FR901228, which has been s hown to specifically inhibit expression of c-myc in fibroblasts, We fo und that FR901228 could effectively block activation-induced apoptosis in T cell hybridomas and this was correlated with its specific inhibi tion of c-myc expression, Both FR901228 and antisense oligodeoxynucleo tide to c-myc had similar effect in inhibiting Fast expression. These treatments did not affect activation-induced production of IL-2, nor t he expression of Fas, In addition, FR901228 inhibited the expression o f Fast in 3T3 fibroblasts, but not these transfected with c-myc, suppo rting a specific role of c-myc in this process. Thus, c-Myc plays a fu ndamental role in the regulation of the expression of Fast, but not Fa s and IL-2, Our data further defined the requirement of c-Myc in activ ation-induced apoptosis in T cells.