The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Reactive Oxygen Species Promote TNFα-Induced Death and Sustained JNK Activation by Inhibiting MAP Kinase Phosphatases
Open accessAbstract
TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFalpha-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H(2)O(2) accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration.
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In the citing paper
“In general, phosphatases are inhibited by ROS11, whereas kinases may be inhibited or activated12.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [12]
In the citing paper
“In recent years, however, several studies have shown that mtROS production is actively triggered by a number of different stimuli including the recognition of pathogens and pathogen-associated molecular patterns (PAMPs) [30,61] or endogenous molecules such as TNF [48,136].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [48]
In the citing paper
“This pro-oxidant effect blunts the activity of redoxsensitive phosphatases controlling JNK activation [213,214], thus inducing programmed cell death in response to TNF [107,213,215].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [214]
In the citing paper
“Although some increases in ROS can stimulate these essential pathways, there is a threshold range of concentrations beyond which ROS become harmful (83, 206, 349).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [206]
In the citing paper
“Prolonged JNK activation can also be caused by oxidative inactivation of DUSPs that dephosphorylate JNK (206).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [206]
In the citing paper
“To this end, ROS act as inhibitors of protein phosphatases such as PTEN and PTP1B, as well as activators of Src family kinases and MAPK (Denu and Tanner, 1998; Kamata et al., 2005; Lee et al., 2002; Yan and Berton, 1996).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Kamata et al., 2005
In the citing paper
“The inactivation of MAPK-phosphatases leads to activation of various stress-activated JNK and p38K [104], [105].”
In the citing paper
“Although NF-κB regulates the expression of several anti-apoptotic genes, the key regulator of NF-κB-mediated inhibition of the JNK pathway is the mitochondrial antioxidant protein SOD2 53.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [53]
In the citing paper
“Since then, ROS have been shown to inhibit other classes of phosphatases, including phosphatase and tensin homolog (PTEN, lipid phosphatase) and MAPK phosphatases 51–53.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [53]
In the citing paper
“Cells without intact NF-κB lack SOD2 induction and accumulate ROS at much higher levels than their wild-type counterparts when treated with TNFα, corresponding with increased JNK activation 53, 60.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [53]
In the citing paper
“The mechanism by which SOD2 confers survival to cells treated with TNFα lies in the ability of ROS to inactivate JNK phosphatases 53.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [53]
In the citing paper
“SOD2 provides a protective effect by lowering cellular ROS levels and decreasing JNK activation after TNFα treatment 53.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [53]
In the citing paper
“and enforced expression of SOD2 in the absence of NF-κB can counteract TNFα-induced cell death 53.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [53]
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Metadata
- Authors
- Kamata, H., Honda, S.-I., Maeda, S., Chang, L., Hirata, H., & Karin, M.
- Affiliations
- University of Hyogo (JP)
- University of California San Diego (US)
- Corresponding author
- Karin, Michael
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 120
- Issue
- 5
- Pages
- 649-661
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2114111268
- Cited by
- 1,792
- References
- 4
- Citations by year
- 2026: 30 · 2025: 41 · 2024: 49 · 2023: 56 · 2022: 56 · 2021: 82 · 2020: 74 · 2019: 74 · 2018: 65 · 2017: 94 · 2016: 80 · 2015: 88 · 2014: 98 · 2013: 97 · 2012: 94
- FWCI
- 46.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5P42 ES10337, AI43477, ES04151, ES06376)
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology (16570121)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- reactive oxygen species, TNF-α, JNK activation, MAP kinase phosphatase, cysteine oxidation, sulfenic acid, mitochondrial superoxide dismutase, NF-κB, cytochrome c release, caspase-3, necrosis, antioxidants, acute liver failure, liver regeneration, oxidative stress
- MeSH terms
- Animals, Antioxidants, Chlorocebus aethiops, Enzyme Activation, HeLa Cells, Humans, Hydrogen Peroxide, Necrosis, Oxidation-Reduction, Phosphoric Monoester Hydrolases, Sulfenic Acids, Superoxide Dismutase, Tumor Necrosis Factor-alpha, Cell Death, Liver Failure, Acute, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, COS Cells, Caspases, Cytochromes c, JNK Mitogen-Activated Protein Kinases, Mice, Caspase 3
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