Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

Abstract

The nuclear factor-jB (NF-jB) signalling pathway serves a crucial role in regulating the transcriptional responses of physiological processes that include cell division, cell survival, differentiation, immunity and inflammation. Here we outline studies using mouse models in which the core components of the NF-jB pathway, namely the IjB kinase subunits (IKKa, IKKb and NEMO), the IjB proteins (IjBa, IjBb, IjBe and Bcl-3) and the five NF-jB transcription factors (NF-jB1, NF-jB2, c-Rel, RelA and RelB), have been genetically manipulated using transgenic and knockout technology.

Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

“…27 This phenotype was reproduced in mice with constitutive global deletion of ikk␤ or NEMO, confirming that the IKK/NF-B system plays a critical role in hepatocyte survival, at least during embryogenesis. 28 At the same time, data from in vitro studies with human HCC cell lines consistently demonstrate that NF-B is cytoprotective via its ability to prevent apoptosis. Furthermore, the oncogenic HBV protein HBx and the HCV core and NS5B proteins were reported to induce NF-B.…”

Inhibitors of NF-κB signaling: 785 and counting

“…In addition, specific C-terminal Ser to Ala mutations are sometimes included to reduce the constitutive turnover of IkBa (van Antwerp et al, 1996). Such SR molecules have been used successfully to inhibit NF-kB activity in a variety of in vitro cell culture studies (e.g., van Antwerp et al, 1996;Wang et al, 1996;Bushdid et al, 1998;Kanegae et al, 1998) and in several in vivo transgenic mouse studies (see Gerondakis et al, 2006). In general, the use of the IkBa-SR has been taken as one of the best evidences for the involvement of NF-kB in a given physiological process; however, because IkBa does not bind well to RelB-containing complexes, the IkBa-SR is probably primarily a blocker of the canonical NF-kB pathway.…”

“…For example, as described above, IKKa and IKKb are active as dimers. However, they appear to have distinct physiological functions in that disruption of each IKK gene in mice leads to quite different phenotypes (Gerondakis et al, 2006). Furthermore, IKKa and IKKb can be activated independently by different upstream signals.…”

Transcriptional regulation via the NF-κB signaling module

“…These stimuli may trigger inflammation, innate immune responses, adaptive immune responses, secondary lymphoid organ development and osteoclastogenesis. Studies with knockout mice have revealed NF-kB's critical involvement in all of these processes (Gerondakis et al, 2006). NF-kB was first identified as a biochemical activity capable of binding to a 10 base pairs (bp) sequence within the transcriptional enhancer of the immunoglobulin (Ig) k light chain gene.…”