CROSS-TALK BETWEEN CELL-DEATH AND CELL-CYCLE PROGRESSION - BCL-2 REGULATES NFAT-MEDIATED ACTIVATION

BCL-2-deficient T cells demonstrate accelerated cell cycle progression and increased apoptosis following activation. Increasing the levels o f BCL-2 retarded the G(0) --> S transition, sustained the levels of cy clin-dependent kinase inhibitor p27(Kip1), and repressed postactivatio n death. Proximal signal transduction events and immediate early gene transcription were unaffected. However, the transcription and synthesi s of interleukin 2 and other delayed early cytokines were markedly att enuated by BCL-2. In contrast, a cysteine protease inhibitor that also blocks apoptosis had no substantial affect upon cytokine production. Interleukin 2 expression requires several transcription factors of whi ch nuclear translocation of NFAT (nuclear factor of activated T cells) and NFAT-mediated transactivation were impaired by BCL-2. Thus, selec t genetic aberrations in the apoptotic pathway reveal a cell autonomou s coregulation of activation.