Functions of NF-κB1 and NF-κB2 in immune cell biology

Abstract

Two members of the NF-kappaB (nuclear factor kappaB)/Rel transcription factor family, NF-kappaB1 and NF-kappaB2, are produced as precursor proteins, NF-kappaB1 p105 and NF-kappaB2 p100 respectively. These are proteolytically processed by the proteasome to produce the mature transcription factors NF-kappaB1 p50 and NF-kappaB2 p52. p105 and p100 are known to function additionally as IkappaBs (inhibitors of NF-kappaB), which retain associated NF-kappaB subunits in the cytoplasm of unstimulated cells. The present review focuses on the latest advances in research on the function of NF-kappaB1 and NF-kappaB2 in immune cells. NF-kappaB2 p100 processing has recently been shown to be stimulated by a subset of NF-kappaB inducers, including lymphotoxin-beta, B-cell activating factor and CD40 ligand, via a novel signalling pathway. This promotes the nuclear translocation of p52-containing NF-kappaB dimers, which regulate peripheral lymphoid organogenesis and B-lymphocyte differentiation. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas. NF-kappaB1 has a distinct function from NF-kappaB2, and is important in controlling lymphocyte and macrophage function in immune and inflammatory responses. In contrast with p100, p105 is constitutively processed to p50. However, after stimulation with agonists, such as tumour necrosis factor-alpha and lipopolysaccharide, p105 is completely degraded by the proteasome. This releases associated p50, which translocates into the nucleus to modulate target gene expression. p105 degradation also liberates the p105-associated MAP kinase (mitogen-activated protein kinase) kinase kinase TPL-2 (tumour progression locus-2), which can then activate the ERK (extracellular-signal-regulated kinase)/MAP kinase cascade. Thus, in addition to its role in NF-kappaB activation, p105 functions as a regulator of MAP kinase signalling.

Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-κB and upregulation of BCL-2 and BCL-XL

“…Previous reports demonstrated that NF-kB is an important transcriptional regulator of Bcl-2 and Bcl-XL (Mori et al, 2001;Sevilla et al, 2001;Bharti and Aggarwal, 2002;Beinke and Ley, 2004;Panwalkar et al, 2004). NF-kB is a family of transcription factors composed of homo-and heterodimers of Rel family polypeptides: p50, p52, RelA (p65), RelB and c-Rel (Rel) (Bharti and Aggarwal, 2002;Beinke and Ley, 2004;Panwalkar et al, 2004).…”

“…NF-kB is a family of transcription factors composed of homo-and heterodimers of Rel family polypeptides: p50, p52, RelA (p65), RelB and c-Rel (Rel) (Bharti and Aggarwal, 2002;Beinke and Ley, 2004;Panwalkar et al, 2004). In non-simulated cells, NF-kB is inactivated by binding to IkB in the cytoplasm.…”

“…In non-simulated cells, NF-kB is inactivated by binding to IkB in the cytoplasm. On apoptotic stimulation, however, proteolytic degradation of IkB unmasks a nuclear target sequence within NF-kB and leads to its translocation to the nucleus, where it induces transcription of various genes, including antiapoptotic Bcl-2 and Bcl-XL (Baldwin, 1996;Pahl, 1999;Catz and Johnson, 2001;Bharti and Aggarwal, 2002;Beinke and Ley, 2004;Panwalkar et al, 2004). The p50/RelA (p65) heterodimer, 'specifically' known as NF-kB, is the most common dimer, and the most important transcriptional regulator playing a major antiapoptotic role in anticancer drug-treated mammalian cells (Baeuerle and Henkel, 1994;Ghosh et al, 1998;Panwalkar et al, 2004).…”

BAFF and the plasticity of peripheral B cell tolerance

“…A separate study by Enzler et al showed that all major components of the non-classical NF-κB pathway are crucial for BAFF-mediated survival [26•]. Further, while knockout mice for the components of each pathway differ slightly, all are essentially similar to BAFF −/− or BAFFr −/− mice [20,[34][35][36]. Thus, it seems likely that the BCR and BAFFr are coupled through these two signaling systems, either via simultaneous activation targeting separate promoters of survival, or through direct cross-talk.…”

Relationship of the mucosal microbiota to gastrointestinal inflammation and small cell intestinal lymphoma in cats

“…This protein complex is also involved in activation of effector cells through toll‐like receptors (TLRs) in response to GI micro‐organisms. Dysregulation of the activation of NF‐κB can lead to overproduction of pro‐inflammatory cytokines and cell transformation, triggering the development of cancers in humans 25, 26, 27…”