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Integrating cell-signalling pathways with NF-κB and IKK function

Key Points

  • The nuclear factor (NF)-κB, inhibitor of NF-κB (IκB) and IκB kinase (IKK) pathway is activated in response to various stimuli in many cell types. NF-κB is activated by many mechanisms, including the canonical pathway, which activates the IKK complex and results in the degradation of IκB in response to inflammatory stimuli.

  • Several NF-κB- and IκB-independent substrates for the IKK proteins are now being identified. These indicate that in addition to induction of NF-κB, these kinases might function to programme the overall cellular response to specific activating stimuli.

  • The consequences of NF-κB activation can vary depending on the context in which activation occurs. This modulation is at least in part due to the regulation of NF-κB subunits in the nucleus, where they translocate after release from cytoplasmic IκB proteins.

  • One mechanism of regulating NF-κB subunit function is through post-translational modifications such as phosphorylation and acetylation. This allows other cell-signalling proteins to influence NF-κB function and therefore serves as a mechanism to integrate their activities with the NF-κB and IKK pathway.

  • NF-κB subunits can also bind DNA cooperatively and activate transcription synergistically with heterologous transcription factors. As independent cell-signalling pathways regulate many of these factors, this provides another mechanism through which NF-κB and IKK activity can be integrated with the overall cellular response to multiple stimuli.

  • Feedback loops exist in which the activation of NF-κB target genes can influence the later time points of the NF-κB response to specific cell stimuli.

  • Crosstalk with the Jun N-terminal kinase (JNK), p53 and nuclear-receptor pathways provide specific examples of the diversity of mechanisms that exist to link NF-κB function to other important networks that regulate cell fate, the immune response and inflammation.

  • The complexity of the mechanisms regulating NF-κB function presents both a challenge and an opportunity when seeking to exploit NF-κB function in a clinical setting. Results indicate that care must be taken when using NF-κB or IKK inhibitors in the clinic, but they also indicate that understanding these pathways will improve diagnostic capabilities and maximize the effectiveness of such inhibitors.

Abstract

Nuclear factor (NF)-κB and inhibitor of NF-κB kinase (IKK) proteins regulate many physiological processes, including the innate- and adaptive-immune responses, cell death and inflammation. Disruption of NF-κB or IKK function contributes to many human diseases, including cancer. However, the NF-κB and IKK pathways do not exist in isolation and there are many mechanisms that integrate their activity with other cell-signalling networks. This crosstalk constitutes a decision-making process that determines the consequences of NF-κB and IKK activation and, ultimately, cell fate.

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Figure 1: The mammalian members of the NF-κB, IκB and IKK families.
Figure 2: The consequences of IKKβ activation.
Figure 3: The consequences of IKKα activation.
Figure 4: Crosstalk between the NF-κB and JNK-signalling pathways.
Figure 5: Integration of the p53 pathway with the function of the RelA (p65) NF-κB subunit.
Figure 6: Crosstalk between the NF-κB and nuclear-receptor pathways.

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Acknowledgements

My apologies for any relevant reports I was unable to cite, either due to lack of space, the need to selectively choose examples or my oversight. Thanks to Cameron Bracken, Kirsteen Campbell, John O'Shea, Katie Schumm and Sonia Rocha for their critical reading of the manuscript and all members of the N.D.P. laboratory for their help and support. Research in the author's laboratory is supported by a programme grant from Cancer Research UK together with funding from the Association of International Cancer Research (AICR) and the Wellcome Trust.

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DATABASES

Entrez Gene

HDM2

HMG-I

IκBα

IκBβ

IκBε

IKK1

IKK2

NEMO

p100

p105

RelA

RelB

FURTHER INFORMATION

Neil D. Perkins's homepage

Glossary

Co-activators and co-repressors

Transcriptional regulatory proteins that are typically recruited to promoters and enhancers by interacting with DNA-bound transcription factors. Co-activators stimulate transcription whereas co-repressors do the opposite. Co-activators are frequently histone acetyltransferases whereas co-repressors are often histone deacetylases.

Checkpoint kinases

The checkpoint kinases ATM and ATR are differentially activated in response to distinct forms of genotoxic stress. Generally, ATR and ATM activate the downstream checkpoint kinases CHK1 and CHK2, respectively. Together these kinases help orchestrate the cellular response to DNA damage.

14-3-3 proteins

A large eukaryotic class of proteins that are involved in cell division, apoptosis, signal transduction, transmitter release, receptor function, gene expression and enzyme activation. They function by binding to various different, specific target proteins, usually in response to phosphorylation of these targets.

Type-2 diabetes

Diabetes that results from insulin resistance or from reduced production of insulin.

bHLH transcription factor

A transcription factor containing a DNA-binding and dimerization domain characterized by a region of basic amino acids followed by a helix–loop–helix motif.

Cyclin D1

A cyclin that forms heterodimers with the cyclin-dependent kinases CDK4 or CDK6, thereby regulating transition through the G1 phase. Cyclin D1 also has CDK-independent functions and can function as a regulator of transcription.

β-catenin

A dual-function protein that has a role in the cytoplasm regulating cell adhesion and a role in the nucleus as a transcriptional co-activator that mediates the Wnt-signal-transduction pathway. Frequently mutated in cancer, β-catenin can function as an oncogene.

E2F1

A member of the E2F family of transcription factors, which, together with the retinoblastoma tumour suppressor, regulate genes that control cell-cycle progression and DNA synthesis.

CBP and p300

CBP and p300 are highly homologous transcriptional co-activator proteins with histone acetyltransferase domains. Both interact with various transcription factors.

bZIP-motif-containing transcription factor

A transcription factor that contains a DNA-binding and dimerization domain characterized by a region of basic amino acids followed by a leucine-zipper motif.

Jun, ATF, CREB and Fos family

A transcription factor family, members of which all contain related bZIP domains and form homo- and heterodimers that bind related DNA sequences. Collectively, dimers of Jun and Fos family members are often referred to as the AP1 transcription factor.

Kruppel-like factor

A protein that is homologous to the Kruppel transcription factor, originally characterized in Drosophila melanogaster. Kruppel-like factors possess zinc-finger-containing DNA-binding domains.

MADS box

The MADS box is a conserved DNA-binding motif originally identified in the MCM1, AG, DEFA and SRF proteins, from which it derives its name.

IRF3

A transcription factor that regulates genes that contain the interferon-sensitive response element (ISRE) sequence. IRF3 activity can be induced through binding of LPS to Toll-like receptor-4, which also activates NF-κB.

E3 ubiquitin ligase

A protein that directly interacts with target proteins and catalyses their ubiquitylation. Lys48-linked ubiquitylation can lead to proteasomal degradation whereas Lys63- linked ubiquitylation can facilitate protein interactions and activation of signalling pathways.

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Perkins, N. Integrating cell-signalling pathways with NF-κB and IKK function. Nat Rev Mol Cell Biol 8, 49–62 (2007). https://doi.org/10.1038/nrm2083

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