NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis.
Recent evidence indicates that the transcription factor NF-kappaB is a major effector of inducible antiapoptotic mechanisms. For example, it was shown that NF-kappaB 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-kappaB controls other key regulatory mechanisms in apoptosis. Here we show that NF-kappaB activation suppresses mitochondrial release of cytochrome c through the activation of the Bcl-2 family member A1/Bfl-1. The restoration of A1 in NF-kappaB 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-kappaB and establish that the prosurvival function of NF-kappaB can be manifested at multiple levels.
Wang
C Y
CY
Laboratory of Molecular Signaling and Apoptotsis, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA. cywang@umich.edu
Guttridge
D C
DC
Mayo
M W
MW
Baldwin
A S
AS
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D015342:DNA Probes / Q000235:genetics; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D015778:Minor Histocompatibility Antigens; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; C096816:BCL2-related protein A1; D003574:Cytochrome c Group; D015342:DNA Probes; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases