NF-kappa B induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis

Recent evidence indicates that the transcription factor NF-kappa B is a maj or effector of inducible antiapoptotic mechanisms. For example, it was show n that NF-kappa B activation suppresses the activation of caspase 8, the ap ical caspase in tumor necrosis factor (TNF) receptor family signaling casca des, through the transcriptional regulation of certain TRAF and IAP protein s. However, it was unknown whether NF-kappa B controls other key regulatory mechanisms in apoptosis. Here we show that NF-kappa B activation suppresse s mitochondrial release of cytochrome c through the activation of the Bcl-2 family member A1/Bfl-1. The restoration of A1 in NF-kappa B null cells dim inished TNF-induced apoptosis by reducing the release of proapoptotic cytoc hrome c from mitochondria. In addition, A1 potently inhibited etoposide-ind uced apoptosis by inhibiting the release of cytochrome c and by blocking ca spase 3 activation. Our findings demonstrate that A1 is an important antiap optotic gene controlled by NF-kappa B and establish that the prosurvival fu nction of NF-kappa B can be manifested at multiple levels.