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

Abstract

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.

RelB regulates manganese superoxide dismutase gene and resistance to ionizing radiation of prostate cancer cells

“…It has been reported that the p100 protein can have a p53-dependent proapoptotic function (Wang et al, 2002). However, this is not likely to be the case in our study for several reasons.…”

Parenchymal regression in chronic pancreatitis spares islets reprogrammed for the expression of NFκB and IAPs

“…13 It was, however, also suggested that NFkB2 (p100) might be a direct activator of programmed cell death. 14,15 NFkB was shown to be involved in acute pancreatitis. 16 Activation of NFkB was detected as early as 10 min after supramaximal stimulation in the cerulein model of acute pancreatitis and seemed to limit the damage induced, while blocking NFkB activation had an adverse effect.…”

Mutations in the NF-κB signaling pathway: implications for human disease

“…In short, these p100 truncations may promote the activity of the non-canonical p52-RELB NF-kB pathway. However, the C-terminal truncations in p100 also remove a caspase-8 recruitment 'death domain' (Wang et al, 2002), suggesting that these p100 truncations could also contribute to oncogeneis by rendering cells more resistant to apoptotic stimuli.…”