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Missing Pieces in the NF-κB Puzzle
Open accessAbstract
The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.
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“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 [2020]
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Self-citationNF-κB at the crossroads of life and death
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Self-citationTAK1 is a ubiquitin-dependent kinase of MKK and IKK
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“Several protein kinases, including CKII, GSK3, PKC , PKC , IKK , and IKK regulate the activity of NF B, though the precise mechanisms in some cases is not clear (Ghosh and Karin, 2002).”
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“Interestingly, however, although IL-1 is known to be a potent regulator of gene transcription, exerting its effects via activation of transcription factors including NF- B and AP-1 (Ghosh and Karin, 2002; O’Neill, 2002), the mechanism underlying its structural effects has remained unresolved (Liu et al.”
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“Although translocation of p50/p65 dimers is mostly d pendent on phosphorylation of IκB by the IKKβ subunit of the IKK complex, activation of p52/RelB relies on p100 phosphorylation by the IKKα subunit (Ghosh and Karin, 2002).”
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“These kinases phosphorylate I B , leading to its polyubiquitination and degradation at the proteasome 26S (Ghosh and Karin, 2002), allowing NF- B to migrate to the nucleus and activate transcription of proinflammatory genes.”
African swine fever virus proteins involved in evading host defence systems
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“B is a dimeric inflammatory transcription factor that requires the p65-p50 isoform for translocation to the nucleus (Ghosh and Karin, 2002).”
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Self-citationSignaling Role of Intracellular Iron in NF-κB Activation
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“Consequently, an elevated activation of NF-κB has been related to age-associated diseases that course with inflammation [3,11,85], wherein, in addition, and given the crucial role of NF-κB in other diverse biological processes, including immune response, macrophage polarization toward an inflammatory M1 phenotype, tel…”
Glycogen Synthase Kinase-3β Regulates NF-κB1/p105 Stability
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“It is becoming increasingly clear that NF-B can modulate multiple aspects of cell growth and death ( 10 ).”
BackgroundAdipocyte differentiation induces dynamic changes in NF-κB expression and activity
Berg, A. H., Lin, Y., Lisanti, M. P., & Scherer, P. E. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00002.2004 · Cited by 160
Zhao, G., Xu, M., Zhao, M., Dai, X.-Y., Kong, W., Wilson, G. M., Guan, Y., Wang, C., & Wang, X. (2012) · Kidney International · doi:10.1038/ki.2012.40 · Cited by 160
“In mammalian cells, classical NF-κB is a heterodimer of p50 and p65/RelA proteins, in which the p65/RelA subunit has transactivation activity (9, 10).”
Bacterial Effector Binding to Ribosomal Protein S3 Subverts NF-κB Function
Gao, X., Wan, F., Mateo, K. S., Callegari, E. A., Wang, D., Deng, W., Puente, J. L., Li, F., Chaussee, M. S., Finlay, B. B., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000708 · Cited by 160
“I k B a masks the nuclear localization signal (NLS) of p65, yet leaves the p50 nuclear localization signal exposed, permitting flux of I k B a / NF-k B complexes between the nucleus and the cytoplasm [17].”
Watanabe, T., Nishio, H., Tanigawa, T., Yamagami, H., Okazaki, H., Watanabe, K., Tominaga, K., Fujiwara, Y., Oshitani, N., Asahara, T., et al. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90553.2008 · Cited by 160
“Upon stimulation, I- B is phosphorylated, ubiquitinated, and degraded by the proteasome, allowing NF- B to translocate to the nucleus (7).”
Novel functions for NFκB: inhibition of bone formation
Krum, S. A., Chang, J., Miranda‐Carboni, G. A., & Wang, C. (2010) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2010.133 · Cited by 160
“133" language="eng" publish="issue" relation="no"> Introduction The transcription factor NFκB represents a family of five mammalian proteins (c-Rel, RelA, RelB, NFκB1 and NFκB2) that regulate a wide variety of genes involved in immune and inflammatory responses, among many other functions”
BackgroundS-nitrosylation: Physiological regulation of NF-κB
Marshall, H. E., Hess, D. T., & Stamler, J. S. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403034101 · Cited by 160
Rajendrasozhan, S., Yang, S., Edirisinghe, I., Yao, H., Adenuga, D., & Rahman, I. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1938 · Cited by 160
“NF-(cid:2) B is a family of seven structurally related transcription factors (p50, p105, p52, p100, RelA/p65, C-Rel, and RelB) that play a central role in inflammation and stress response by controlling gene network expression (30).”
Visekruna, A., Joeris, T., Seidel, D., Kroesen, A. J., Loddenkemper, C., Zeitz, M., Kaufmann, S. H. E., Schmidt‐Ullrich, R., & Steinhoff, U. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28804 · Cited by 159
Zhang, X.-A., Zhang, S., Yin, Q., & Zhang, J. (2015) · Pharmacognosy Magazine · doi:10.4103/0973-1296.153096 · Cited by 167
“Once activated, NF‐κB stimulates the transcription of genes encoding cytokines, growth factors, chemokines, and anti‐apoptotic factors.[18,19] Moreover, NF‐κB pathway has also been implicated in tumor initiation, progression, metastasis, and resistance to chemotherapy.”
Gao, M., & Karin, M. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.08.017 · Cited by 163
Self-citationNF-κB in Mammary Gland Development and Breast Cancer
Cao, Y., & Karin, M. (2003) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1023/a:1025905008934 · Cited by 160
Self-citationTargeting NF-κB in hematologic malignancies
Braun, T., Carvalho, G., Fabre, C., Grosjean, J., Fenaux, P., & Kroemer, G. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401874 · Cited by 158
Karunaweera, N., Raju, R., Gyengési, E., & nch, G. M. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00024 · Cited by 164
“…cytokines (e.g., IL-1, IL-2, IL-6 and TNF-α), adhesion molecules (e.g., ICAM, VCAM, E-selectin) as well as inducible pro-inflammatory enzymes (COX-2 and iNOS), which exacerbate and perpetuate the inflammatory process (Barnes, 1997; Ghosh and Karin, 2002; Figuera-Losada et al., 2014).”
Real-time imaging of ligand-induced IKK activation in intact cells and in living mice
Gross, S., & Piwnica-Worms, D. R. (2005) · Nature Methods · doi:10.1038/nmeth779 · Cited by 157
Minimal model of spiky oscillations in NF-κB signaling
Krishna, S., Jensen, M. H., & Sneppen, K. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604085103 · Cited by 160
Mechanisms of Proinflammatory Cytokine-Induced Biphasic NF-κB Activation
Schmidt, C., Peng, B., Li, Z., Sclabas, G. M., Fujioka, S., Niu, J., Schmidt‐Supprian, M., Evans, D. B., Abbruzzese, J. L., & Chiao, P. J. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00390-3 · Cited by 157
O‐GlcNAcylation of TAB1 modulates TAK1‐mediated cytokine release
Pathak, S., Borodkin, V. S., Albarbarawi, O., Campbell, D. G., Ibrahim, A. F. M., & van Aalten, D. M. F. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.8 · Cited by 156
“In the canonical NF k B activation pathway, upon phosphorylation by IKK b , I kba and I k B b , the cytoplasmic inhibitors of NF k B, are marked for ubiquitination and subsequent proteosomal degradation (DiDonato et al , 1996; Ghosh and Karin, 2002).”
Agarwal, S., Deschner, J., Long, P., Verma, A., Hofman, C., Evans, C. H., & Piesco, N. P. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20601 · Cited by 156
Ser276 Phosphorylation of NF-kB p65 by MSK1 Controls SCF Expression in Inflammation
Reber, L. L., Vermeulen, L., Haegeman, G., & Frossard, N. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004393 · Cited by 156
“The nuclear factor-kB (NF-kB) family is composed of homodimers and heterodimers of the Rel family proteins, including p65 (RelA), c-Rel, RelB, p52 and p50 (for review, see [1]).”
Liu, B., Yang, Y., Chernishof, V., Loo, R. R. O., Jang, H., Tahk, S., Yang, R., Mink, S. R., Shultz, D. B., Bellone, C. J., et al. (2007) · Cell · doi:10.1016/j.cell.2007.03.056 · Cited by 156
Metadata
- Authors
- Ghosh, S., & Karin, M.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California San Diego (US)
- Corresponding author
- Ghosh, Sankar
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2002-04
- Volume
- 109
- Issue
- 2
- Pages
- S81-S96
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1976382352
- Cited by
- 3,638
- References
- 158
- Citations by year
- 2026: 29 · 2025: 65 · 2024: 66 · 2023: 49 · 2022: 66 · 2021: 94 · 2020: 100 · 2019: 84 · 2018: 103 · 2017: 111 · 2016: 122 · 2015: 141 · 2014: 134 · 2013: 144 · 2012: 189
- FWCI
- 19.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- NF-κB, IκB kinase complex, transcription factor regulation, transcriptional activity, IκB, signal transduction
- MeSH terms
- Animals, Cell Nucleus, Cytoplasm, Enzyme Activation, Gene Expression Regulation, Humans, Signal Transduction, NF-kappa B, Protein Serine-Threonine Kinases, Catalytic Domain, Active Transport, Cell Nucleus, I-kappa B Kinase
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