NF-κB2 p100 is a pro-apoptotic protein with anti-oncogenic function

Nuclear factor-kappaB (NIF-kappaB) promotes cell survival by upregulating expression of anti-apoptotic genes, a process that is antagonized by inhibitors of kappaB (IkappaB) factors(1) The only NF-kappaB family member known to be mutated in human cancer is NF-kappaB2 p100 (ref. 2), a factor with IkappaB 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 IkappaB-like activity. The carboxyl terminus of p100 contains a death domain(3) 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 IkappaB-independent apoptotic activity of NF-kappaB2 p100 and help explain its unique tumour suppressor role.