Cited by 2,738Cell death mechanisms and regulationNF-κB Signaling PathwaysImmune Response and Inflammation

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Induction of TNF Receptor I-Mediated Apoptosis via Two Sequential Signaling Complexes

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Micheau, Olivier, Tschopp, Jürg·2003·Cell

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Abstract

Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.

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Authors: Micheau, O., & Tschopp, J.
Affiliations: University of Lausanne (CH)
Corresponding author: Tschopp, Jürg
ORCID: Micheau, Olivier
Venue: Cell
Publisher: Elsevier BV
Published: 2003-07
Volume: 114
Issue: 2
Pages: 181-190
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/s0092-8674(03)00521-x
OpenAlex: W2114727688
Cited by: 2,738
References: 40
Citations by year: 2026: 91 · 2025: 103 · 2024: 113 · 2023: 132 · 2022: 152 · 2021: 129 · 2020: 132 · 2019: 107 · 2018: 112 · 2017: 123 · 2016: 132 · 2015: 123 · 2014: 139 · 2013: 125 · 2012: 144
FWCI: 33.67
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3669 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion, other-oa)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Topics: 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
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: TNF receptor 1, apoptosis, TRADD, RIPK1, TRAF2, FADD, caspase-8, FLIP(L), NF-κB activation, cell survival, receptor signaling complex
MeSH terms: Carrier Proteins, Cell Membrane, Cell Survival, Cytoplasm, Humans, Models, Biological, Proteins, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Signal Transduction, Transcriptional Activation, NF-kappa B, RNA-Binding Proteins, Apoptosis, Receptors, Tumor Necrosis Factor, fas Receptor, Jurkat Cells, Caspases, Nuclear Pore Complex Proteins, Intracellular Signaling Peptides and Proteins, TNF Receptor-Associated Factor 1, Adaptor Proteins, Signal Transducing, Caspase 8, Fas-Associated Death Domain Protein, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspase 9, Caspase Inhibitors

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Induction of TNF Receptor I-Mediated Apoptosis via Two Sequential Signaling Complexes

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