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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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“Under basal conditions NF-kB is inactive, bound by inhibitory kappa B (IkB), which sequesters NF-kB in cytoplasm by blocking its nuclear localization signal (Ghosh and Karin, 2002; Jacobs and Harrison, 1998).”
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“Moreover, the efficient transcriptional activation of NF-kB depends on the phosphorylation of its active subunit p65/RelA (Ghosh and Karin, 2002).”
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“CD40L and, to a greater extent, BAFF also activate IKK through NF-B-inducing kinase (NIK) ( 34 , 35).”
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“A number of recent studies support the conjecture that RelA phosphorylation may be necessary for transcriptional competence of NF-kB (Ghosh and Karin, 2002, and references therein). In the model, we simply assume that the NF-kB is in a state in which it is capable of regulating transcription. The two recent experiment…”
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“NF-κB is tightly controlled by the IκB kinase complex IKKα in response to cytokine treatment (Ghosh and Karin, 2009).”
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“Recent studies have shown that posttranslational modification of NF B subunits, such as p65, contributes significantly to NF B transactivation potential (Ghosh and Karin, 2002).”
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“Upon cytokine signaling, innate or adaptive immune responses, or environmental stress NF-kB activation is initiated (3).”
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“In both cases, the necrotic death of hepatocytes was found to result in the release of IL-1a, which then activates MyD88-dependent NF-kB signaling in Kupffer cells, leading to IL-6 induction (Sakurai et al., 2008).”
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“…and NF-kB pathways (Lee et al., 1999; Chen C et al., 2000; Chen Q et al., 2000; Manna et al., 2000; Sevilla et al., 2001; Dixit and Mak, 2002; Ghosh and Karin, 2002; Karin and Lin, 2002) formulating the hypothesis of the subsequent studies that entails rituximab may inhibit the constitutive…”
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InfluentialSelf-citationExpression and function of Toll-like receptors in chicken heterophils
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InfluentialInhibition of the Ubiquitin-Proteasome System Induces Stress Granule Formation
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“However, with other stresses such as UV treatment, GCN2 plays the opposite role by activating the anti-apoptotic NF B pathways (Ghosh and Karin, 2002).”
BackgroundModulation of transcription factor function by O-GlcNAc modification
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“This leads to dissociation and translocation of NF-κB into the nucleus and activation of target genes [59,61].”
Apoptosis: biochemical aspects and clinical implications
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“…known to play roles in a diverse array of cellular and physiological functions, including apoptosis, proliferation, cell adhesion, migration, inflammatory and adaptive immune responses (reviewed in Ghosh et al., 1998; Karin and Ben-Neriah, 2000; Silverman and Maniatis, 2001; Ghosh and Karin, 2002).”
BackgroundNF‐κB as a potential molecular target for cancer therapy
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“Furthermore, the NF-kB-IkB complex had already been found to shuttle between the cytoplasm and the nucleus in the absence of signal (Johnson et al., 1999; Carlotti et al., 2000; Ghosh and Karin, 2002).”
BackgroundSuppression of PTEN Expression by NF-κB Prevents Apoptosis
Vasudevan, K. M., Gurumurthy, S., & Rangnekar, V. M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.3.1007-1021.2004 · Cited by 247
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NF‐κB: A Multifaceted Transcription Factor Regulated at Several Levels
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Dual Roles for Immunity in Gastrointestinal Cancers
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“NF- B proteins are normally retained in the cytoplasm through a set of inhibitory proteins, but following receptor-mediated activation of I B kinases (IKK), the inhibitors are degraded, thereby allowing nuclear import of the transcription factors.(17) Studies of mice deficient in IKK- have revealed a critical role for…”
Positive and negative regulation of EAAT2 by NF‐κB: a role for N‐myc in TNFα‐controlled repression
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“…family of transcription factors, which are ubiquitously expressed and are pivotal in control- ling diverse cellular processes, including immune responses, cell proliferation and differentiation (Israel, 2000; Baldwin, 2001; Silverman and Maniatis, 2001; Ghosh and Karin, 2002; Li and Verma, 2002).”
BackgroundPinning down cell signaling, cancer and Alzheimer's disease
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The role of Toll-like receptors in the host response to viruses
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Transcriptional networks in developing and mature B cells
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The Transcription Factor Nuclear Factor-kappa B and Cancer
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Apoptotic cells induce Mer tyrosine kinase–dependent blockade of NF-κB activation in dendritic cells
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NFκB pathway: A good signaling paradigm and therapeutic target
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Role of nuclear factor κB in cardiovascular health and disease
der Heiden, K. V., Cuhlmann, S., Luong, L. A., Zakkar, M., & Evans, P. C. (2010) · Clinical Science · doi:10.1042/cs20090557 · Cited by 241
Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury
Pettus, E. H., Wright, D. W., Stein, D. G., & Hoffman, S. W. (2005) · Brain Research · doi:10.1016/j.brainres.2005.05.004 · Cited by 235
Kataoka, T., & Tschopp, J. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.7.2627-2636.2004 · Cited by 235
“The NF-B signaling pathway is regulated by the cytosolicnuclear shuttling and modulation of the transcriptional activity ( 12 ).”
BackgroundTCR-Mediated Notch Signaling Regulates Proliferation and IFN-γ Production in Peripheral T Cells
Palaga, T., Miele, L., Golde, T. E., & Osborne, B. A. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.6.3019 · Cited by 235
Bhat, A. A., Nisar, S., Singh, M. K., Ashraf, B., Masoodi, T., Prasad, C. P., Sharma, A., Maacha, S., Karedath, T., Hashem, S., et al. (2022) · 癌症:英文版 · doi:10.1002/cac2.12295 · Cited by 251
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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