ArticleCell death and differentiation2017
STAT1 mediates transmembrane TNF-alpha-induced formation of death-inducing signaling complex and apoptotic signaling via TNFR1.
Article in Cell death and differentiation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- TNFα-Related Chondrocyte Inflammation Models: A Systematic Review.International journal of molecular sciences · 2024Pooled it
- Effect of pearl millet diet on immunomodulating factors, physical performance and recovery in athletes: a randomised control trial.Scientific reports · 2026Trial
- Bugs as drugs: parasite biomolecules as novel therapeutics against breast cancer.American journal of physiology. Cell physiology · 2026Review
- The mechanism and clinical research of vagus nerve electrical stimulation in the treatment of myocardial ischemia-reperfusion injury.iScience · 2026Review
- Acupuncture-induced HSP70 upregulation in neuroprotection: mitochondrial and anti-apoptotic mechanisms.American journal of translational research · 2026Review
- Inflammatory and Immune Pathways Driving Tumor Necrosis Factor Inhibitor Resistance in Ulcerative Colitis.Journal of inflammation research · 2026Review
- Differences in Immunological and Inflammatory Biomarkers Levels in People Infected withAdvanced biomedical research · 2026Article
- Proinflammatory macrophage secretome enhances temozolomide sensitivity in glioblastoma via pSTAT3-mediated downregulation of DNA repair enzymes.Scientific reports · 2025Article
- Inhibition of ATM enhances the immunogenicity of triple-negative breast cancer by promoting MHC-I expression.Cell death & disease · 2025Article
- Osteoarthritis: Mechanisms and Therapeutic Advances.MedComm · 2025Review
- Oleic acid restores the impaired antitumor immunity of γδ-T cells induced by palmitic acid.Signal transduction and targeted therapy · 2025Article
- Astaxanthin prevents postovulatory oocyte aging by targeting TNFR2 and inhibiting the TNF signaling pathway.BMC biology · 2025Article
- The Role of TNF-α in Neuropathic Pain: An Immunotherapeutic Perspective.Life (Basel, Switzerland) · 2025Review
- Inflammation and cancer cell survival: TRAF2 as a key player.Cell death & disease · 2025Review
- Evaluation of Methods Employed in Establishing Preclinical Similarity of Adalimumab Biosimilars.Advances in pharmacological and pharmaceutical sciences · 2025Review
- Controversies and insights into cytokine regulation of neurogenesis and behavior in adult rodents.Frontiers in immunology · 2025Review
- TNF-ɑ induces mitochondrial dysfunction to drive NLRP3/Caspase-1/GSDMD-mediated pyroptosis in MCF-7 cells.Scientific reports · 2024Article
- PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Beyond CAR-T: The rise of CAR-NK cell therapy in asthma immunotherapy.Journal of translational medicine · 2024Review
- Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumor necrosis factor-alpha (TNF-α) exists in two forms: secretory TNF-α (sTNF-α) and transmembrane TNF-α (tmTNF-α). Although both forms of TNF-α induce tumor cell apoptosis, tmTNF-α is able to kill tumor cells that are resistant to sTNF-α-mediated cytotoxicity, indicating their differences in signal transduction. Here, we demonstrate that internalization of TNFR1 is crucial for sTNF-α- but not for tmTNF-α-induced apoptosis. sTNF-α induces binding of tumor necrosis factor receptor type 1-associated death domain protein (TRADD) to the death domain (DD) of TNFR1 and subsequent activation of nuclear factor kappa B (NF-κB), and the formation of death-inducing signaling complexes (DISCs) in the cytoplasm after internalization. In contrast, tmTNF-α induces DISC formation on the membrane in a DD-independent manner. It leads to the binding of signal transducer and activator of transcription 1 (STAT1) to a region spanning amino acids 319-337 of TNFR1 and induces phosphorylation of serine at 727 of STAT1. The phosphorylation of STAT1 promotes its binding to TRADD, and thus recruits Fas-associated protein with DD (FADD) and caspase 8 to form DISC complexes. This STAT1-dependent signaling results in apoptosis but not NF-κB activation. STAT1-deficiency in U3A cells counteracts tmTNF-α-induced DISC formation and apoptosis. Conversely, reconstitution of STAT1 expression restores tmTNF-α-induced apoptotic signaling in the cell line. Consistently, tmTNF-α suppresses the growth of STAT1-containing HT1080 tumors, but not of STAT1-deficient U3A tumors in vivo. Our data reveal an unappreciated molecular mechanism of tmTNF-α-induced apoptosis and may provide a new clue for cancer therapy.
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