NF-κB Induces Expression of the Bcl-2 Homologue A1/Bfl-1 To Preferentially Suppress Chemotherapy-Induced Apoptosis

Abstract

Recent evidence indicates that the transcription factor NF-κB is a major effector of inducible antiapoptotic mechanisms. For example, it was shown that NF-κB activation suppresses the activation of caspase 8, the apical caspase in tumor necrosis factor (TNF) receptor family signaling cascades, through the transcriptional regulation of certain TRAF and IAP proteins. However, it was unknown whether NF-κB controls other key regulatory mechanisms in apoptosis. Here we show that NF-κB activation suppresses mitochondrial release of cytochrome cthrough the activation of the Bcl-2 family member A1/Bfl-1. The restoration of A1 in NF-κB null cells diminished TNF-induced apoptosis by reducing the release of proapoptotic cytochrome c from mitochondria. In addition, A1 potently inhibited etoposide-induced apoptosis by inhibiting the release of cytochrome c and by blocking caspase 3 activation. Our findings demonstrate that A1 is an important antiapoptotic gene controlled by NF-κB and establish that the prosurvival function of NF-κB can be manifested at multiple levels.

ACKNOWLEDGMENTS

We gratefully acknowledge Aly Karsan for the kind gift of the A1 cDNA.

Research support was provided by NIH grant DE12823 to C.-Y.W., by NCI grant CA75080 to A.S.B. and M.W.M., by American Cancer Society grant PF9903801 to D.G., and by NIH grant AI35098 and NCI grants CA73756 and CA72771 to A.S.B.