ArticleMolecular and cellular biology2015
RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival.
Article in Molecular and cellular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 35 citations in OpenAlex.
- Monogenic disorders of the TNF signalling pathway.Nature reviews. Rheumatology · 2026Review
- IBCar: Potent Orally Bioavailable MethylCancers · 2025Article
- A bacterial effector manipulates host lysosomal protease activity-dependent plasticity in cell death modalities to facilitate infection.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- N4BP1 functions as a dimerization-dependent linear ubiquitin reader which regulates TNF signalling.Cell death discovery · 2024Article
- Review
- Induction of Breast Cancer Cell Apoptosis by TRAIL and Smac Mimetics: Involvement of RIP1 and cFLIP.Current issues in molecular biology · 2022Article
- Aluminum Induced Necroptosis of PC12 Cells via TNFR1-RIP1/RIP3 Signalling Pathway.Neurochemical research · 2022Article
- Cell death in skin function, inflammation, and disease.The Biochemical journal · 2022Review
- The lncRNA CASC2 Modulates Hepatocellular Carcinoma Cell Sensitivity and Resistance to TRAIL Through Apoptotic and Non-Apoptotic Signaling.Frontiers in oncology · 2021Article
- Article
- Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease.Nature reviews. Rheumatology · 2020Review
- Hidden Aspects of Valency in Immune System Regulation.Trends in immunology · 2019Review
- Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform.PLoS computational biology · 2019Article
- ISG12a and its interaction partner NR4A1 are involved in TRAIL-induced apoptosis in hepatoma cells.Journal of cellular and molecular medicine · 2019Article
- TRAILblazing Strategies for Cancer Treatment.Cancers · 2019Review
- TRAF2 Controls Death Receptor-Induced Caspase-8 Processing and Facilitates Proinflammatory Signaling.Frontiers in immunology · 2019Article
- Developing TRAIL/TRAIL death receptor-based cancer therapies.Cancer metastasis reviews · 2018Review
- Cell Death Pathways: a Novel Therapeutic Approach for Neuroscientists.Molecular neurobiology · 2018Review
- Targeting CAND1 promotes caspase-8/RIP1-dependent apoptosis in liver cancer cells.American journal of translational research · 2018Article
- Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Although TRAIL is considered a potential anticancer agent, it enhances tumor progression by activating NF-κB in apoptosis-resistant cells. Cellular FLICE-like inhibitory protein (cFLIP) overexpression and caspase-8 activation have been implicated in TRAIL-induced NF-κB activation; however, the underlying mechanisms are unknown. Here, we report that caspase-8-dependent cleavage of RIP1 in the kinase domain (KD) and intermediate domain (ID) determines the activation state of the NF-κB pathway in response to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment. In apoptosis-sensitive cells, caspase-8 cleaves RIP1 in the KD and ID immediately after the recruitment of RIP1 to the receptor complex, impairing IκB kinase (IKK) recruitment and NF-κB activation. In apoptosis-resistant cells, cFLIP restricts caspase-8 activity, resulting in limited RIP1 cleavage and generation of a KD-cleaved fragment capable of activating NF-κB but not apoptosis. Notably, depletion of the cytoplasmic pool of TRAF2 and cIAP1 in lymphomas by CD40 ligation inhibits basal RIP1 ubiquitination but does not prompt cell death, due to CD40L-induced cFLIP expression and limited RIP1 cleavage. Inhibition of RIP1 cleavage at the KD suppresses NF-κB activation and cell survival even in cFLIP-overexpressing lymphomas. Importantly, RIP1 is constitutively cleaved in human and mouse lymphomas, suggesting that cFLIP-mediated and caspase-8-dependent limited cleavage of RIP1 is a new layer of mechanism that promotes NF-κB activation and lymphoma survival.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.