AP-1 FACTORS PLAY AN IMPORTANT ROLE IN TRANSFORMATION-INDUCED BY THE V-REL ONCOGENE

v-rel is the oncogenic member of the Rel/NF-kappa B family of transcri ption factors. The mechanism by which v-Rel induces transformation of avian lymphoid cells and fibroblasts is not precisely known. However, most models propose that v-rel disrupts the normal transcriptional reg ulatory network. In this study we evaluated the role of Ap-1 family me mbers in v-Rel-mediated transformation. The overexpression of v-Rel, c -Rel, and c-Rel Delta resulted in a prolonged elevation of c-fos and c -jun expression and in a sustained repression of fra-2 at both the mRN A and protein levels in fibroblasts and lymphoid cells. Moreover, the transforming abilities of these Rel proteins correlated with their abi lity to alter the expression of these AP-1 factors. v-Rel exhibited th e most pronounced effect, whereas c-Rel, with poor transforming abilit y, elicited only moderate changes in AP-1 levels. Furthermore, c-Rel D elta, which exhibits enhanced transforming potential relative to c-Rel , induced intermediate changes in AP-1 expression. To directly evaluat e the role of AP-1 family members in the v-Rel transformation process, a supjun-1 transdominant mutant was used. The supjun-1 mutant functio ns as a general inhibitor of AP-1 activity by inhibiting AP-1-mediated transactivation and by reducing AP-1 DNA-binding activity. Coinfectio n or sequential infection of fibroblasts or lymphoid cells with viruse s carrying rel oncogenes and supjun-1 resulted in a reduction of the t ransformation efficiency of the Rel proteins. The expression of supjun -1 inhibited the ability of v-Rel transformed lymphoid cells and fibro blasts to form colonies in soft agar by over 70%. Furthermore, the exp ression of supjun-1 strongly interfered with the ability of v-Rel to m orphologically transform avian fibroblasts. This is the first report s howing that v-Rel might execute its oncogenic potential through modula ting the activity of early response genes.