Reactive oxygen species are downstream products of TRAF-mediated signal transduction
Open accessAbstract
Members of the TNFR (tumor necrosis factor receptor) superfamily are involved in regulating activation and differentiation of cells as well as cell survival and programmed cell death/apoptosis. Multimerization of TNFRs can lead to recruitment of TRAFs (TNFR-associated factors) by the receptors resulting in activation of kinases and transcription factors, such as c-Jun N-terminal kinase and nuclear factor kappaB (NF-kappaB). Signal transduction triggered by TNF-alpha also induces an increase in intracellular reactive oxygen species (ROS). ROS have been suggested to play a role in NF-kappaB activation, which is thought to promote cell survival. However, oxidation of proteins and lipids by ROS can also result in apoptosis. The processes generating intracellular ROS and the mechanism(s) regulating the cellular redox status have not been fully elucidated. We investigated whether TRAFs play a role in controlling intracellular ROS levels. Our results indicate that recruitment of TRAFs to the plasma membrane of human embryonic kidney (HEK) 293 cells is crucial for activation of signaling pathways, which regulate ROS production in mitochondria. TRAF-mediated changes in ROS levels enhanced NF-kappaB activation but were not dependent on NF-kappaB-inducing kinase. Consistent with its anti-apoptotic function, Bcl-x(L) interfered with TRAF-mediated ROS generation but not NF-kappaB activation. Taken together, our results suggest a novel role of TRAFs in signal transduction pathways triggered by TNFR-related proteins, which balance cell survival and apoptosis by regulating the electron transport in mitochondria.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Upon treatment with TNFα, mitochondrial production of ROS is increased.
“Upon treatment with TNFα, mitochondrial production of ROS is increased 59.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [59]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Death Receptors: Signaling and Modulation
Ashkenazi, A., & Dixit, V. M. (1998) · Science · doi:10.1126/science.281.5381.1305 · Cited by 5,866 · see citing works
Schreck, R., RIEBER, P., & Baeuerle, P. A. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb07761.x · Cited by 3,816 · see citing works
The TNF and TNF Receptor Superfamilies
Locksley, R. M., Killeen, N., & Lenardo, M. J. (2001) · Cell · doi:10.1016/s0092-8674(01)00237-9 · Cited by 3,650 · see citing works
Karin, M., Liu, Z.-G., & Zandi, E. (1997) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(97)80068-3 · Cited by 2,904 · see citing works
LeBel, C. P., Ischiropoulos, H., & Bondy, S. C. (1992) · Chemical Research in Toxicology · doi:10.1021/tx00026a012 · Cited by 2,694 · see citing works
Chinnaiyan, A. M., O'Rourke, K., Tewari, M., & Dixit, V. M. (1995) · Cell · doi:10.1016/0092-8674(95)90071-3 · Cited by 2,431 · see citing works
BABIOR, B. M. (1999) · Blood · doi:10.1182/blood.v93.5.1464 · Cited by 2,147 · see citing works
Chandel, N. S., McClintock, D. S., Feliciano, C. E., Wood, T. M., Melendez, J. A., Rodriguez, A. M., & Schumacker, P. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001914200 · Cited by 2,000 · see citing works
Self-citationThe TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death
Smith, C. A., Farrah, T., & Goodwin, R. G. (1994) · Cell · doi:10.1016/0092-8674(94)90372-7 · Cited by 1,909 · see citing works
Human Cells Lacking mtDNA: Repopulation with Exogenous Mitochondria by Complementation
King, M. P., & Attardi, G. M. (1989) · Science · doi:10.1126/science.2814477 · Cited by 1,659 · see citing works
Failure to Regulate TNF-Induced NF-κB and Cell Death Responses in A20-Deficient Mice
Lee, E. G., Boone, D. L., Chai, S., Libby, S. L., Chien, M., Lodolce, J. P., & Ma, A. (2000) · Science · doi:10.1126/science.289.5488.2350 · Cited by 1,409 · see citing works
Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation
(1990) · Trends in Genetics · doi:10.1016/0168-9525(90)90040-d · Cited by 1,386 · see citing works
Bcl-xL Regulates the Membrane Potential and Volume Homeostasis of Mitochondria
Heiden, M. G. V., Chandel, N. S., Williamson, E. K., Schumacker, P. T., & Thompson, C. B. (1997) · Cell · doi:10.1016/s0092-8674(00)80450-x · Cited by 1,378 · see citing works
Self-citationMAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1
Malinin, N. L., Boldin, M., Kovalenko, A. V., & Wallach, D. (1997) · Nature · doi:10.1038/385540a0 · Cited by 1,279 · see citing works
Bcl-2 inhibits the mitochondrial release of an apoptogenic protease.
Susín, S. A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, É., Geuskens, M., & Kroemer, G. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.4.1331 · Cited by 1,133 · see citing works
Rothe, M., Wong, S. C., Henzel, W. J., & Goeddel, D. V. (1994) · Cell · doi:10.1016/0092-8674(94)90532-0 · Cited by 1,054 · see citing works
TRAF2-Mediated Activation of NF-κB by TNF Receptor 2 and CD40
Rothe, M., Sarma, V. J., Dixit, V. M., & Goeddel, D. V. (1995) · Science · doi:10.1126/science.7544915 · Cited by 1,050 · see citing works
Rothe, M., Pan, M.-G., Henzel, W. J., Ayres, T. M., & V. Goeddel, D. (1995) · Cell · doi:10.1016/0092-8674(95)90149-3 · Cited by 1,030 · see citing works
Boldin, M. P., Varfolomeev, E. E., Pancer, Z., Mett, I. L., Camonis, J. H., & Wallach, D. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.14.7795 · Cited by 993 · see citing works
Superoxide dismutase as a target for the selective killing of cancer cells
Huang, P., Li, F., Oldham, E. A., Keating, M. J., & Plunkett, W. K. (2000) · Nature · doi:10.1038/35030140 · Cited by 842 · see citing works
Arch, R. H., Gedrich, R. W., & Thompson, C. B. (1998) · Genes & Development · doi:10.1101/gad.12.18.2821 · Cited by 611 · see citing works
Self-citationRole of Oxidants in NF-κB Activation and TNF-α Gene Transcription Induced by Hypoxia and Endotoxin
Chandel, N. S., Trzyna, W., McClintock, D. S., & Schumacker, P. T. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.2.1013 · Cited by 536 · see citing works
Self-citationApoptosis: Activate NF-κB or die?
Baichwal, V. R., & Baeuerle, P. A. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00046-7 · Cited by 528 · see citing works
Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-κb-inducing kinase
Shinkura, R., Kitada, K., Matsuda, F., Tashiro, K., Ikuta, K., Suzuki, M., Kogishi, K., Serikawa, T., & Honjo, T. (1999) · Nature Genetics · doi:10.1038/8780 · Cited by 451 · see citing works
Lee, S. Y., Reichlin, A., Santana, A., Sokol, K. A., Nussenzweig, M. C., & Choi, Y. (1997) · Immunity · doi:10.1016/s1074-7613(00)80390-8 · Cited by 445 · see citing works
Song, H. Y., Rothe, M., & Goeddel, D. V. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.13.6721 · Cited by 414 · see citing works
Defective Lymphotoxin-β Receptor-Induced NF-κB Transcriptional Activity in NIK-Deficient Mice
Li, Y., Wu, L., Wesche, H., Arthur, C. D., White, J. M., Goeddel, D. V., & Schreiber, R. D. (2001) · Science · doi:10.1126/science.1058453 · Cited by 408 · see citing works
THE CENTRAL EFFECTORS OF CELL DEATH IN THE IMMUNE SYSTEM
Rathmell, J. C., & Thompson, C. B. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.781 · Cited by 378 · see citing works
Arch, R. H., & Thompson, C. B. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.1.558 · Cited by 356 · see citing works
Self-citation[75] Assay of transforming activity of tumor virus DNA
van der Eb, A. J., & Graham, F. L. (1980) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(80)65077-0 · Cited by 328 · see citing works
Gottlieb, E., Heiden, M. G. V., & Thompson, C. B. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.15.5680-5689.2000 · Cited by 317 · see citing works
Impaired Negative Selection of T Cells in Hodgkin's Disease Antigen CD30–Deficient Mice
Amakawa, R., Hakem, A., Kündig, T. M., Matsuyama, T., Simard, J. J. L., Timms, E. M., Wakeham, A. C., Mittruecker, H., Griesser, H., Takimoto, H., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81031-4 · Cited by 305 · see citing works
TANK, a co-inducer with TRAF2 of TNF- and CD 40L-mediated NF-kappaB activation.Preprint
Cheng, G., & Baltimore, D. (1996) · Genes & Development · doi:10.1101/gad.10.8.963 · Cited by 288 · see citing works
Nemoto, S., DiDonato, J. A., & Lin, A. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.12.7336 · Cited by 224 · see citing works
Induction of Nuclear Factor κB by the CD30 Receptor Is Mediated by TRAF1 and TRAF2
Duckett, C. S., Gedrich, R. W., Gilfillan, M. C., & Thompson, C. B. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.3.1535 · Cited by 216 · see citing works
I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction.
Rothe, M., Xiong, J., Shu, H., Williamson, K., Goddard, A. D., & Goeddel, D. V. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8241 · Cited by 212 · see citing works
Multiple redox regulation in NF-kappaB transcription factor activation.
Piette, J. G., Piret, B., Bonizzi, G., Schoonbroodt, S., Merville, M., Legrand-Poels, S., & Bours, V. (1997) · PubMed · Cited by 212 · see citing works
Redox Signals and NF-κB Activation in T Cells
Ginn‐Pease, M. E., & Whisler, R. L. (1998) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(98)00067-7 · Cited by 206 · see citing works
Kawamata, S., Hori, T., Imura, A., Takaori‐Kondo, A., & Uchiyama, T. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.10.5808 · Cited by 200 · see citing works
Cells depleted of mitochondrial DNA (p0) yield insight into physiological mechanisms
Chandel, N. S., & Schumacker, P. T. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00783-8 · Cited by 198 · see citing works
Self-citationLee, S. Y., Lee, S. Y., & Choi, Y. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.7.1275 · Cited by 195 · see citing works
Human 4-1BB (CD137) Signals Are Mediated by TRAF2 and Activate Nuclear Factor-κB
Jang, I. K., Lee, Z. H., Kim, Y. J., Kim, S. H., & Kwon, B. S. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.8016 · Cited by 176 · see citing works
Gedrich, R. W., Gilfillan, M. C., Duckett, C. S., Dongen, J. L. V., & Thompson, C. B. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.22.12852 · Cited by 172 · see citing works
Yamada, T., Mitani, T., Yorita, K., Uchida, D., Matsushima, A., Iwamasa, K., Fujita, S., & Matsumoto, M. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.2.804 · Cited by 162 · see citing works
Rao, K. M. K., Padmanabhan, J., Dl, K., Cohen, H. J., Currie, M. S., & Weinberg, J. B. (1992) · Journal of Leukocyte Biology · doi:10.1002/jlb.51.5.496 · Cited by 133 · see citing works
Fagarasan, S., Shinkura, R., Kamata, T., Nogaki, F., Ikuta, K., Tashiro, K., & Honjo, T. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.9.1477 · Cited by 127 · see citing works
Tumor Necrosis Factor (TNF) Receptor 1 Signaling Downstream of TNF Receptor-associated Factor 2
Natoli, G., Costanzo, A., Moretti, F., Fulco, M., Balsano, C., & Levrero, M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.42.26079 · Cited by 114 · see citing works
Chiarle, R., Podda, A., Prolla, G., Podack, E. R., Thorbecke, G. J., & Inghirami, G. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.1.194 · Cited by 106 · see citing works
Metabolism of Rotenone in vitro by Tissue Homogenates from Mammals and Insects
FUKAMI, J.-I., YAMAMOTO, I., & Casida, J. E. (1967) · Science · doi:10.1126/science.155.3763.713 · Cited by 100 · see citing works
Klug, C. A., Gerety, S. J., Shah, P. C., Chen, Y. Y., Rice, N. R., Rosenberg, N. E., & Singh, H. (1994) · Genes & Development · doi:10.1101/gad.8.6.678 · Cited by 79 · see citing works
Pennica, D., Lam, V. T., Mize, N. K., Weber, R. F., Lewis, M., FENDLY, B. M., Lipari, M. T., & Goeddel, D. V. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)36813-9 · Cited by 67 · see citing works
Translocation of TRAF Proteins Regulates Apoptotic Threshold of Cells
Arch, R. H., Gedrich, R. W., & Thompson, C. B. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2873 · Cited by 59 · see citing works
Self-citationLymphocyte Survival—The Struggle Against Death
Arch, R. H., & Thompson, C. B. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.113 · Cited by 46 · see citing works
Self-citationBrodersen, J., Bäumer, S., Abken, H., et al. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00017.x · Cited by 31 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Rothe, M., Xiong, J., Shu, H. B., Williamson, K., Goddard, A., and Goeddel, D. V. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 8241-8246
- Song, H. Y., Rothe, M., and Goeddel, D. V. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 6721-6725
Cited by
Sorted by citations
Physiological Roles of Mitochondrial Reactive Oxygen Species
Sena, L. A., & Chandel, N. S. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.09.025 · Cited by 2,632 · see citing works
Self-citationMitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes
Hamanaka, R. B., & Chandel, N. S. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.04.002 · Cited by 1,011 · see citing works
Self-citationMitochondria in the Regulation of Innate and Adaptive Immunity
Weinberg, S. E., Sena, L. A., & Chandel, N. S. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.002 · Cited by 960 · see citing works
Self-citationOxidative stress in obesity: A critical component in human diseases
Marseglia, L., Manti, S., D’Angelo, G., Nicotera, A., Parisi, E., Di Rosa, G., Gitto, E., & Arrigo, T. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms16010378 · Cited by 933 · see citing works
Pham, C. G., Bubici, C., Zazzeroni, F., Papa, S., Jones, J., Alvarez, K., Jayawardena, S., De Smaele, E., Cong, R., Beaumont, C., et al. (2004) · Cell · doi:10.1016/j.cell.2004.10.017 · Cited by 663 · see citing works
Mitochondria as signaling organelles
Chandel, N. S. (2014) · BMC Biology · doi:10.1186/1741-7007-12-34 · Cited by 576 · see citing works
Self-citationOxidative stress and metabolic pathologies: from an adipocentric point of view
Le Lay, S., Simard, G., Martinez, M. C., & Andriantsitohaina, R. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/908539 · Cited by 291 · see citing works
- Authors
- Chandel, N. S., Schumacker, P. T., & Arch, R. H.
- Affiliations
- University of Chicago (US)
- Washington University in St. Louis (US)
- Corresponding author
- Arch, Robert H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 276
- Issue
- 46
- Pages
- 42728-42736
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2039620761
- Cited by
- 203
- References
- 54
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 7 · 2020: 11 · 2019: 7 · 2018: 10 · 2017: 13 · 2016: 9 · 2015: 2 · 2014: 11 · 2013: 2 · 2012: 7
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- 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
- Keywords
- reactive oxygen species, TRAF, TNF receptor superfamily, signal transduction, NF-κB activation, apoptosis, cell survival, mitochondrial electron transport chain, Bcl-xL, redox regulation, TNF signaling
- MeSH terms
- Bacterial Proteins, Cell Line, Cell Membrane, Cell Survival, Cytoplasm, Electron Transport, Enzyme Activation, Humans, Luciferases, Models, Biological, Oxidation-Reduction, Oxygen, Protein Binding, Subcellular Fractions, Transfection, Blotting, Western, Signal Transduction, NF-kappa B, Apoptosis, Reactive Oxygen Species, Protein Structure, Tertiary, Ki-1 Antigen, CD28 Antigens, Proto-Oncogene Proteins c-bcl-2, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, bcl-X Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
