ArticleThe Journal of biological chemistry2013
Novel phosphorylation and ubiquitination sites regulate reactive oxygen species-dependent degradation of anti-apoptotic c-FLIP protein.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 75 citations in OpenAlex.
- Redox-modulation of regulated cell death: implications for synergistic anticancer therapies.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- c-FLIP as a master regulator of immune homeostasis and disease mechanisms.Cell death & disease · 2026Review
- Quercetin Enhances Topotecan Cytotoxicity in Retinoblastoma Cells Through ROS-Associated Stress and Apoptotic Signaling.Biomolecules · 2026Article
- The Role of Reactive Oxygen Species in Lung Cancer Development: Nanomedicine as a Therapeutic Strategy.Biomolecules · 2025Review
- Reactive Oxygen Species: From Tumorigenesis to Therapeutic Strategies in Cancer.Cancer medicine · 2025Review
- The Role of Post-Translational Modifications in Necroptosis.Biomolecules · 2025Review
- Applications and enhancement strategies of ROS-based non-invasive therapies in cancer treatment.Redox biology · 2025Review
- Epigenetics disruptions enabled by porphyrin-derived metal-organic frameworks disarm resistances to sonocatalytic ROS anti-tumor actions.Fundamental research · 2025Article
- Regulation of anti-tumour effects of Paris polyphylla saponins via ROS: molecular mechanisms and therapeutic potentials.Frontiers in pharmacology · 2025Review
- Review
- Caspase-8 in inflammatory diseases: a potential therapeutic target.Cellular & molecular biology letters · 2024Review
- Oxidative State in Cutaneous Melanoma Progression: A Question of Balance.Antioxidants (Basel, Switzerland) · 2024Review
- Article
- Cellular Dynamics of Fas-Associated Death Domain in the Regulation of Cancer and Inflammation.International journal of molecular sciences · 2024Review
- Sequential Ubiquitination and Phosphorylation Epigenetics Reshaping by MG132-Loaded Fe-MOF Disarms Treatment Resistance to Repulse Metastatic Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.International journal of molecular sciences · 2023Article
- Pyrazolo[4,3-International journal of molecular sciences · 2023Article
- Modulation of redox homeostasis: A strategy to overcome cancer drug resistance.Frontiers in pharmacology · 2023Review
- Anticancer therapeutic effect of ginsenosides through mediating reactive oxygen species.Frontiers in pharmacology · 2023Review
- Restoring TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress as a Therapeutic Strategy in Cancer.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The cytosolic protein c-FLIP (cellular Fas-associated death domain-like interleukin 1β-converting enzyme inhibitory protein) is an inhibitor of death receptor-mediated apoptosis that is up-regulated in a variety of cancers, contributing to apoptosis resistance. Several compounds found to restore sensitivity of cancer cells to TRAIL, a TNF family death ligand with promising therapeutic potential, act by targeting c-FLIP ubiquitination and degradation by the proteasome. The generation of reactive oxygen species (ROS) has been implicated in c-FLIP protein degradation. However, the mechanism by which ROS post-transcriptionally regulate c-FLIP protein levels is not well understood. We show here that treatment of prostate cancer PPC-1 cells with the superoxide generators menadione, paraquat, or buthionine sulfoximine down-regulates c-FLIP long (c-FLIP(L)) protein levels, which is prevented by the proteasome inhibitor MG132. Furthermore, pretreatment of PPC-1 cells with a ROS scavenger prevented ubiquitination and loss of c-FLIP(L) protein induced by menadione or paraquat. We identified lysine 167 as a novel ubiquitination site of c-FLIP(L) important for ROS-dependent degradation. We also identified threonine 166 as a novel phosphorylation site and demonstrate that Thr-166 phosphorylation is required for ROS-induced Lys-167 ubiquitination. The mutation of either Thr-166 or Lys-167 was sufficient to stabilize c-FLIP protein levels in PPC-1, HEK293T, and HeLa cancer cells treated with menadione or paraquat. Accordingly, expression of c-FLIP T166A or K167R mutants protected cells from ROS-mediated sensitization to TRAIL-induced cell death. Our findings reveal novel ROS-dependent post-translational modifications of the c-FLIP protein that regulate its stability, thus impacting sensitivity of cancer cells to TRAIL.
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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.