B-LYMPHOCYTES DIFFERENTIALLY USE THE REL AND NUCLEAR FACTOR KAPPA-B1 (NF-KAPPA-B1) TRANSCRIPTION FACTORS TO REGULATE CELL-CYCLE PROGRESSIONAND APOPTOSIS IN QUIESCENT AND MITOGEN-ACTIVATED CELLS

Rel and nuclear factor (NF)-kappa B1, two members of the Rel/NF-kappa B transcription factor family, are essential for mitogen-induced B cel l proliferation. Using mice with inactivated Rel or NF-kappa B1 genes, we show that these transcription factors differentially regulate cell cycle progression and apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell turnover in naive nfkb1(-/-) mice, the level of apoptosis in cultures of quiescent nfkb1(-/-), but not c-rel (-/-), B cells is higher. The failure of c-rel(-/-) or nfkb1(-/-) B ce lls to proliferate in response to particular mitogens coincides with a cell cycle block early in G1 and elevated cell death. Expression of a bcl-2 transgene prevents apoptosis in resting and activated c-rel(-/- ) and nfkb1(-/-) B cells, but does not overcome the block in cell cycl e progression, suggesting that the impaired proliferation is not simpl y a consequence of apoptosis and that Rel/NF-kappa B proteins regulate cell survival and cell cycle control through independent mechanisms. In contrast to certain B lymphoma cell lines in which mitogen-induced cell death can result from Rel/NF-kappa B-dependent downregulation of c-myc, expression of c-myc is normal in resting and stimulated c-rel(- /-) B cells, indicating that target gene(s) regulated by Rel that are important for preventing apoptosis may differ in normal and immortaliz ed B cells. Collectively, these results are the first to demonstrate t hat in normal B cells, NF-kappa B1 regulates survival of cells in GO, whereas mitogenic activation induced by distinct stimuli requires diff erent Rel/NF-kappa B factors to control cell cycle progression and pre vent apoptosis.