BCL-2 DOWN-REGULATES THE ACTIVITY OF TRANSCRIPTION FACTOR NF-KAPPA-B INDUCED UPON APOPTOSIS

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 t hat NF-kappa B is potently activated upon serum starvation, a conditio n leading to apoptosis in 293 cells. Similar to Bcl-2, a transdominant -negative mutant of the NF-kappa B p65 subunit partially inhibited apo ptosis, 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 over expressed Bcl-2 had the same effect. The transcription inhibitory acti vity of the two proteins correlated with their cell death protective p otential. Like Bcl-2, the related protein Bcl-x(L) but not Bcl-x(S) wa s able to suppress kappa B-dependent transcription. Bcl-2 inhibited NF -kappa B activity by an unusual mechanism. It did not prevent the rele ase of I kappa B in the cytoplasm but down-modulated the transactivati ng potential of nuclear p65. These data show that NF-kappa B can parti cipate in apoptosis. We suggest that at least part of the anti-apoptot ic potential of Bcl-2 may be explained from a hitherto undiscovered ac tivity of Bcl-2 in controlling nuclear gene expression.