Good cop, bad cop: the different faces of NF-κB

Perkins, N D; Gilmore, T D

doi:10.1038/sj.cdd.4401838

Cited by 496NF-κB Signaling PathwaysSignaling Pathways in DiseaseTGF-β signaling in diseases

Good cop, bad cop: the different faces of NF-κB

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Perkins, N D, Gilmore, T D·2006·Cell Death & Differentiation

DOI 10.1038/sj.cdd.4401838

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Abstract

Complexes formed from the nuclear factor kappaB (NF-kappaB) family of transcription factors are ubiquitously expressed and are induced by a diverse array of stimuli. This results in their becoming activated in a wide variety of different settings. While the functions of NF-kappaB in many of these contexts have been the subject of intense research and are now well established, it is also clear that there is great diversity in the effects and consequences of NF-kappaB activation. NF-kappaB subunits do not necessarily regulate the same genes, in an identical manner, in all of the different circumstances in which they are induced. This review will discuss the different functions of NF-kappaB, the pathways that modulate NF-kappaB subunit activity and, in contrast to its more commonly thought of role as a promoter of cancer cell growth and survival, the ability of NF-kappaB, under some circumstances, to behave as a tumor suppressor.

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In the NF-κB system, NF-κB is normally held inactive in the cytoplasm by binding to an inhibitor IκB; pro-inflammatory cytokines such as TNF-α, LPS and IL-1 act by binding to receptors at the cell surface and initiating signalling pathways that lead to activation of IKK; IKK phosphorylates IκB causing its release and degradation, allowing NF-κB to translocate to the nucleus where it can activate a
“In the NF-κB system (e.g. [2020-2024]) (Fig 8), NF-κB is normally held inactive in the cytoplasm by binding to an inhibitor IκB (often IκBα). Pro-inflammatory cytokines such as TNF-α, LPS [2025-2030] and IL-1 [2031] act by binding to receptors at the cell surface and initiating signalling pathways that lead to the activation of a particular kinase, IκB kinase or IKK. This kinase phosphorylates the”
From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [2024]

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Deng, J., Xia, W., Miller, S. A., Wen, Y., Wang, H., & Hung, M. (2004) · Molecular Carcinogenesis · doi:10.1002/mc.10169 · Cited by 85 · see citing works
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Immortalized embryonic mouse fibroblasts lacking the RelA subunit of transcription factor NF-κB have a malignantly transformed phenotype
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Tyrosine Phosphorylation of IkB-a Activates NF-kB without Proteolytic Degradation of IkB-a
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Immortalized fibroblasts from NF-κB RelA knockout mice show phenotypic heterogeneity and maintain increased sensitivity to tumor necrosis factor α after transformation by v-Ras
Gapuzan, M.-E. R., Schmah, O., Pollock, A. D., Hoffmann, A., & Gilmore, T. D. (2005) · Oncogene · doi:10.1038/sj.onc.1208809 · Cited by 41 · see citing works
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Loss of Nuclear Factor-κB Is Tumor Promoting but Does Not Substitute for Loss of p53
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A Dual Role for IKK a in Tooth Development
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Impaired inhibition of NF-κB activity by melanoma-associated p16INK4a mutations
Becker, T. M., Rizos, H., Peña, A., Leclercq, I. A., Woodruff, S., Kefford, R. F., & Mann, G. J. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.032 · Cited by 17 · see citing works
Inverse correlation between p16INK4A expression and NF-κB activation in melanoma progression
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Mutations within a conserved protein kinase A recognition sequence confer temperature-sensitive and partially defective activities onto mouse c-Rel
Gapuzan, M.-E. R., Pitoc, G. A., & Gilmore, T. D. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01123-9 · Cited by 8 · see citing works
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Crosstalk of reactive oxygen species and NF-κB signaling
Morgan, M. J., & Liu, Z.-G. (2011) · Cell Research · doi:10.1038/cr.2010.178 · Cited by 3,505 · see citing works
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Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway
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Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging
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Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases
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Transcriptional profiling of the LPS induced NF-κB response in macrophages
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Oxidative Stress, Plant Natural Antioxidants, and Obesity
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Current insights into the regulation of programmed cell death by NF-κB
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Autophagy in cancer associated fibroblasts promotes tumor cell survival
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Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo.
Zabolotny, J. M., Kim, Y.-B., Welsh, L. A., Kershaw, E. E., Neel, B. G., & Kahn, B. B. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800061200 · Cited by 404 · see citing works
Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance
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Nuclear Factor-κB in Development, Prevention, and Therapy of Cancer
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Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives
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Mitochondria and Reactive Oxygen Species: Physiology and Pathophysiology
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The role of Nuclear Factor-kappa B signaling in human cervical cancer
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IκB kinase β (IKKβ/IKK2/IKBKB)—A key molecule in signaling to the transcription factor NF-κB
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Telomerase: central regulator of all of the hallmarks of cancer
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NF-κB signaling is key in the wound healing processes of silk fibroin
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Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes
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Mechanism of Hypoxia-Induced NF-κB
Culver, C. A., Sundqvist, A., Mudie, S., Melvin, A., Xirodimas, D. P., & Rocha, S. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00409-10 · Cited by 229 · see citing works
Regulation of Nuclear Factor-KappaB (NF-κB) signaling pathway by non-coding RNAs in cancer: Inhibiting or promoting carcinogenesis?
Mirzaei, S., Zarrabi, A., Hashemi, F., Zabolian, A., Saleki, H., Ranjbar, A., Saleh, S. H. S., Bagherian, M., Sharifzadeh, S. O., Hushmandi, K., et al. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.03.025 · Cited by 214 · see citing works
Caffeine effects on systemic metabolism, oxidative-inflammatory pathways, and exercise performance
Barcelos, R. P., Lima, F. D., de Carvalho, N. R., Bresciani, G., & Royes, L. F. F. (2020) · Nutrition Research · doi:10.1016/j.nutres.2020.05.005 · Cited by 222 · see citing works
Small Molecule NF-κB Pathway Inhibitors in Clinic
Ramadass, V., Vaiyapuri, T., & Tergaonkar, V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21145164 · Cited by 214 · see citing works
Evasion of Apoptosis as a Cellular Stress Response in Cancer
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ATM- and NEMO-Dependent ELKS Ubiquitination Coordinates TAK1-Mediated IKK Activation in Response to Genotoxic Stress
Wu, Z.-H., Wong, E. T., Shi, Y., Niu, J., Chen, Z. J., Miyamoto, S., & Tergaonkar, V. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.010 · Cited by 207 · see citing works
Targeting dysregulation of redox homeostasis in noise-induced hearing loss: Oxidative stress and ROS signaling
Fetoni, A. R., Paciello, F., Rolesi, R., Paludetti, G., & Troiani, D. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.02.022 · Cited by 201 · see citing works
Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked
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Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression
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Requirement of the NF-κB Subunit p65/RelA for K-Ras–Induced Lung Tumorigenesis
Bassères, D. S., Ebbs, A., Levantini, E., & Baldwin, A. S. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4290 · Cited by 189 · see citing works
The complex interplay between autophagy and NF-κB signaling pathways in cancer cells.
Trocoli, A., & Djavaheri‐Mergny, M. (2011) · PubMed Central · Cited by 177 · see citing works
The role of hypoxia in inflammatory disease (Review)
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Loss of Epithelial RelA Results in Deregulated Intestinal Proliferative/Apoptotic Homeostasis and Susceptibility to Inflammation
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Evolutionary Conserved Regulation of HIF-1β by NF-κB
van Uden, P., Kenneth, N. S., Webster, R., Müller, H. A., Mudie, S., & Rocha, S. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001285 · Cited by 163 · see citing works
PUMA is directly activated by NF-κB and contributes to TNF-α-induced apoptosis
Wang, P., Qiu, W., Dudgeon, C., Liu, H., Huang, C., Zambetti, G. P., Yu, J., & Zhang, L. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.51 · Cited by 159 · see citing works
Interleukin‐10 provides direct trophic support to neurons
Zhou, Z., Peng, X., Insolera, R., Fink, D. J., & Mata, M. M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06263.x · Cited by 156 · see citing works
Hypoxia Induced NF-κB
D’Ignazio, L., & Rocha, S. (2016) · Cells · doi:10.3390/cells5010010 · Cited by 156 · see citing works
Insights into the behaviour of systems biology models from dynamic sensitivity and identifiability analysis: a case study of an NF-κB signalling pathway
Yue, H., Brown, M., Knowles, J. D., Wang, H., Broomhead, D. S., & Kell, D. B. (2006) · Molecular BioSystems · doi:10.1039/b609442b · Cited by 148 · see citing works
Upregulation of Twist-1 by NF-κB Blocks Cytotoxicity Induced by Chemotherapeutic Drugs
Pham, C. G., Bubici, C., Zazzeroni, F., Knabb, J. R., Papa, S., Kuntzen, C., & Franzoso, G. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01219-06 · Cited by 143 · see citing works
Targeting apoptosis pathways in pancreatic cancer
Arlt, A., Müerköster, S. S., & Schäfer, H. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.10.015 · Cited by 143 · see citing works
Microglia-derived TNFα induces apoptosis in neural precursor cells via transcriptional activation of the Bcl-2 family member Puma
Guadagno, J., Xu, X., Karajgikar, M., Brown, A. M., & Cregan, S. P. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.59 · Cited by 139 · see citing works
Anti-inflammatory effects of ginsenoside Rg1 and its metabolites ginsenoside Rh1 and 20(S)-protopanaxatriol in mice with TNBS-induced colitis
Lee, S., Jeong, J.-J., Eun, S.-H., & Kim, D. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.06.011 · Cited by 141 · see citing works
Regulation of Programmed Cell Death by NF-κB and its Role in Tumorigenesis and Therapy
Fan, Y., Dutta, J., Gupta, N., Fan, G., & Gélinas, C. (2007) · Advances in experimental medicine and biology · doi:10.1007/978-1-4020-6554-5_11 · Cited by 137 · see citing works
Azithromycin Polarizes Macrophages to an M2 Phenotype via Inhibition of the STAT1 and NF-κB Signaling Pathways
Haydar, D., Cory, T. J., Birket, S. E., Murphy, B. S., Pennypacker, K. R., Sinai, A. P., & Feola, D. J. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801228 · Cited by 136 · see citing works
Regulation of p53 tumour suppressor target gene expression by the p52 NF‐κB subunit
Schumm, K., Rocha, S., Caamaño, J., & Perkins, N. D. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601343 · Cited by 135 · see citing works
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Inhibitory kappa B kinases as targets for pharmacological regulation
Gamble, C., McIntosh, K., Scott, R., Ho, K. H., Plevin, R. J., & Paul, A. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01608.x · Cited by 132 · see citing works
Ionizing radiation-induced NF-κB activation requires PARP-1 function to confer radioresistance
Veuger, S. J., Hunter, J. E., & Durkacz, B. W. (2008) · Oncogene · doi:10.1038/onc.2008.439 · Cited by 132 · see citing works
Nucleolar NF-κB/RelA mediates apoptosis by causing cytoplasmic relocalization of nucleophosmin
Khandelwal, N., Simpson, J., Taylor, G., Rafique, S., Whitehouse, A., Hiscox, J. A., & Stark, L. A. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.79 · Cited by 131 · see citing works
HIF-1α restricts NF-κB dependent gene expression to control innate immunity signals
Bandarra, D., Biddlestone, J., Mudie, S., Müller, H. ‐. J., & Rocha, S. (2014) · Disease Models & Mechanisms · doi:10.1242/dmm.017285 · Cited by 130 · see citing works
IKKβ and NF-κB Transcription Govern Lymphoma Cell Survival through AKT-Induced Plasma Membrane Trafficking of GLUT1
Sommermann, T. G., O’Neill, K. E., Plas, D. R., & Cahir-McFarland, E. D. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1715 · Cited by 129 · see citing works
Gene regulation by melatonin linked to epigenetic phenomena
Korkmaz, A., Rosales‐Corral, S., & Reiter, R. J. (2012) · Gene · doi:10.1016/j.gene.2012.04.040 · Cited by 127 · see citing works
The Trypanosoma cruzi Protease Cruzain Mediates Immune Evasion
Doyle, P. S., Zhou, Y. M., Hsieh, I., Greenbaum, D. C., McKerrow, J. H., & Engel, J. C. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002139 · Cited by 126 · see citing works
Targeting apoptosis pathways in cancer stem cells
Signore, M., Ricci‐Vitiani, L., & Maria, R. D. (2011) · Cancer Letters · doi:10.1016/j.canlet.2011.01.013 · Cited by 122 · see citing works
Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry
Deriziotis, P., André, R., Smith, D. M., Goold, R., Kinghorn, K. J., Kristiansen, M., Nathan, J. A., Rosenzweig, R., Krutauz, D., Glickman, M. H., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.224 · Cited by 122 · see citing works
Anti-tumor activity of non-steroidal anti-inflammatory drugs: Cyclooxygenase-independent targets
Liggett, J. L., Zhang, X., Eling, T. E., & Baek, S. J. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.01.021 · Cited by 121 · see citing works
<scp>NF</scp>‐κB as the mediator of metformin's effect on ageing and ageing‐related diseases
Kanigur Sultuybek, G., Soydas, T., & Yenmis, G. (2019) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13073 · Cited by 119 · see citing works
Patchouli alcohol, an essential oil of Pogostemon cablin, exhibits anti-tumorigenic activity in human colorectal cancer cells
Jeong, J. B., Choi, J., Lou, Z., Jiang, X., & Lee, S. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2013.04.006 · Cited by 119 · see citing works
Aurora Kinase A Promotes Inflammation and Tumorigenesis in Mice and Human Gastric Neoplasia
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Authors: Perkins, N. D., & Gilmore, T. D.
Affiliations: University of Dundee (GB)
Boston University (US)
Corresponding author: Perkins, N D
ORCID: Perkins, N D
Gilmore, T D
Venue: Cell Death & Differentiation
Publisher: Springer Science and Business Media LLC
Published: 2006-01-13
Volume: 13
Issue: 5
Pages: 759-772
ISSN: 1350-9047 (ISSN-L)
1476-5403
DOI: 10.1038/sj.cdd.4401838
OpenAlex: W1533671266
Cited by: 489
References: 103
Citations by year: 2026: 9 · 2025: 12 · 2024: 22 · 2023: 21 · 2022: 15 · 2021: 21 · 2020: 23 · 2019: 13 · 2018: 19 · 2017: 24 · 2016: 19 · 2015: 30 · 2014: 38 · 2013: 22 · 2012: 26
FWCI: 2.37
Type: journal article
Language: en
Open access: green
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Cell Death and Differentiation (publishedVersion)
PubMed (publishedVersion)
Newcastle University ePrints (Newcastle Univesity)
Funders: Wellcome Trust
Cancer Research UK
Royal Society
National Institutes of Health
National Cancer Institute (CA 47763)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords: NF-κB, transcription factors, tumor suppression, gene expression regulation, NF-κB subunits
MeSH terms: Carcinogens, Humans, Models, Biological, Neoplasms, Signal Transduction, NF-kappa B, Tumor Suppressor Proteins, I-kappa B Kinase

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