Bcl-2 down-regulates the activity of transcription factor NF-kappaB induced upon apoptosis.

Abstract

Among the many target genes of the transcription factor NF-kappa B are p53 and c-myc, both of which are involved in apoptosis. This prompted us to investigate the role of NF-kappa B in this process. We report that NF-kappa B is potently activated upon serum starvation, a condition leading to apoptosis in 293 cells. Similar to Bcl-2, a transdominant-negative mutant of the NF-kappa B p65 subunit partially inhibited apoptosis, indicating a direct involvement of the transcription factor in induction of cell death. As expected, the p65 mutant suppressed kappa B-dependent gene expression. Surprisingly, transiently or stably overexpressed Bcl-2 had the same effect. The transcription inhibitory activity of the two proteins correlated with their cell death protective potential. Like Bcl-2, the related protein Bcl-x(L) but not Bcl-x(S) was able to suppress kappa B-dependent transcription. Bcl-2 inhibited NF-kappa B activity by an unusual mechanism. It did not prevent the release of I kappa B in the cytoplasm but down-modulated the transactivating potential of nuclear p65. These data show that NF-kappa B can participate in apoptosis. We suggest that at least part of the anti-apoptotic potential of Bcl-2 may be explained from a hitherto undiscovered activity of Bcl-2 in controlling nuclear gene expression.