NF-kappa B2 p100 is a pro-apoptotic protein with anti-oncogenic function.
Nuclear factor-kappa B (NF-kappa B) promotes cell survival by upregulating expression of anti-apoptotic genes, a process that is antagonized by inhibitors of kappa B (I kappa B) factors. The only NF-kappa B family member known to be mutated in human cancer is NF-kappa B2 p100 (ref. 2), a factor with I kappa B activity. Here, we report the isolation from irradiated mouse tumour cells of a complex that induces caspase-8 activity in cell-free assays and identify p100 as an essential component of this complex. Expression of p100 profoundly sensitizes cells to death-receptor-mediated apoptosis through a pathway that is independent of I kappa B-like activity. The carboxyl terminus of p100 contains a death domain that is absent from all known tumour-derived mutants. This death domain mediates recruitment of p100 into death machinery complexes after ligand stimulation and is essential for p100's pro-apoptotic activity. p100 also sensitizes NIH3T3 cells to apoptosis triggered by oncogenic Ras, resulting in a marked inhibition of transformation that is rescued by suppression of endogenous caspase-8. These observations thus identify an I kappa B-independent apoptotic activity of NF-kappa B2 p100 and help explain its unique tumour suppressor role.
Wang
Yongqing
Y
Department of Biochemistry and Molecular Biology, Medical College of Ohio, 3035 Arlington Avenue, Toledo, OH 43614, USA.
Cui
Hongjuan
H
Schroering
Allen
A
Ding
Jane L
JL
Lane
William S
WS
McGill
Gaël
G
Fisher
David E
DE
Ding
Han-Fei
HF
D000818:Animals; D017209:Apoptosis; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D002474:Cell-Free System; D003124:Colorimetry; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D015151:Immunoblotting; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D052003:NF-kappa B p52 Subunit; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D003513:Cycloheximide; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases