A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-κB
Abstract
The signaling pathway through which ionizing radiation induces NF-kappaB activation is not fully understood. IkappaB-alpha, an inhibitory protein of NF-kappaB mediates the activation of NF-kappaB in response to various stimuli, including cytokines, mitogens, oxidants and other stresses. We have now identified an ionizing radiation-induced signaling pathway that is independent of TNF-alpha. IkappaB-alpha degradation is rapid in response to TNF-alpha induction, but it is absent in response to ionizing radiation exposure in cells from individuals with ataxia-telangiectasia (AT). Overexpression of wild-type ATM, the product of the gene defective in AT patients, restores radiation-induced degradation of IkappaB-alpha. Furthermore, phosphorylation of IkappaB-alpha by immunoprecipitated ATM kinase is increased in control fibroblasts and transfected AT cells following ionizing radiation exposure. These data provide support for a novel ionizing radiation-induced signaling pathway for activation of NF-kappaB and a molecular basis for the sensitivity of AT patients to oxidative stresses.
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In AT fibroblasts, NF-kB is activated in an ATM-dependent manner following treatment with a radiomimetic, ionizing radiation, or topoisomerase inhibitor.
“Previous work with AT fibroblasts had shown that the canonical immune transcription factor NF‐kB is activated in an ATM‐dependent manner following treatment with a radiomimetic, ionizing radiation, or topoisomerase inhibitor (Lee et al, 1998; Piret et al, 1999; Li et al, 2001).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Lee et al, 1998
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Deraska, P. V., O’Leary, C., Reavis, H. D., Labe, S. A., Dinh, T.-K. T., Lazaro, J., Sweeney, C. J., D’Andrea, A. D., & Kozono, D. (2018) · Cell Death Discovery · doi:10.1038/s41420-017-0008-3 · Cited by 22 · see citing works
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“It has been suggested that the p38 MAPK is an intermediate player between these two molecules (40, 41) and in our studies the use of the NF-κB inhibitor reduced p-p38 phosphorylation (Figure 4B).”
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Mechanisms of DNA Damage Response to Targeted Irradiation in Organotypic 3D Skin Cultures
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“Nuclear transcription factor kappaB (NF- B) is activated by ionizing radiation and plays a crucial role in mediating radiation induced mucositis [39].”
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“Exposure of cells to ionizing radiation (IR) induces NF-nB activation by a signaling pathway that includes ataxia telangiectasia mutated gene (4), the product of this gene is mutated in individuals with ataxia telangiectasia, a human genetic disease exhibiting extreme sensitivity to IR.”
BackgroundSelf-citationModulation of inflammation and disease tolerance by DNA damage response pathways
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ATM: Sounding the Double-strand Break AlarmPreprint
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Radiation-induced cardiovascular disease: an overlooked role for DNA methylation?
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“[117] Lee S-J, Dimtchev A, Lavin MF, et al.”
NF-κB inhibition enhances caspase-3 degradation of Akt1 and apoptosis in response to camptothecin
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Protection effect of sanguinarine on whole-body exposure of X radiation in BALB/c mice
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“Nuclear factor kappa B (NF-κB) activation, which plays an important role in processes of cell immunity and inflammation, was induced by ionizing radiation (Lee et al., 1998).”
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“…only in various tumour cells, but also in different types of cultured normal cells in vitro (Uckun et al. 1993, Wilson et al. 1993, Mohan and Meltz 1994, Prasad et al. 1994, Weichselbaum et al. 1994, Hallahan et al. 1995, Valerie et al. 1995, Lee et al. 1998, Raju et al. 1998, Yang et al. 2000).”
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“Interestingly, ionizing radiation is known to increase NF-κB signaling which may lead to NF-κBmediated radiation resistance [62, 63].”
Background
- Authors
- Lee, S.-J., Dimtchev, A., Lavin, M. F., Dritschilo, A., & Jung, M.
- Affiliations
- Georgetown University Medical Center (US)
- QIMR Berghofer Medical Research Institute (AU)
- Venue
- Oncogene
- Published
- 1998-10-08
- Volume
- 17
- Issue
- 14
- Pages
- 1821-1826
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2323797330
- Cited by
- 136
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 6 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 5 · 2012: 4
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r29ca063023-01, 5r01ca045408-13)
- National Cancer Institute (CA74175, CA63023, CA-45408, P01CA074175)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- ionizing radiation, NF-κB activation, IκBα degradation, ATM kinase, ataxia telangiectasia, IκBα phosphorylation, oxidative stress sensitivity
- MeSH terms
- Acetylcysteine, Cell Line, DNA-Binding Proteins, Enzyme Inhibitors, Humans, Phosphorylation, Protein-Tyrosine Kinases, Proteins, Tumor Necrosis Factor-alpha, Signal Transduction, Transcriptional Activation, NF-kappa B, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Staurosporine, Genistein, Tumor Suppressor Proteins, I-kappa B Kinase, Ataxia Telangiectasia Mutated Proteins
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