ArticleThe Journal of biological chemistry2011
Cellular FLICE-inhibitory protein (cFLIP) isoforms block CD95- and TRAIL death receptor-induced gene induction irrespective of processing of caspase-8 or cFLIP in the death-inducing signaling complex.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 90 citations in OpenAlex.
- Caspase-activation powers anti-Desmoglein 3-induced acantholysis in human epidermis.Cell death discovery · 2026Article
- Study of TRAIL and SAHA Co-Treatment on Leukemia K562 Cell Line.Cell biochemistry and biophysics · 2025Article
- Biological Functions and Clinical Implications of CFLAR: From Cell Death Mechanisms to Therapeutic Targeting in Immune Regulation.Journal of inflammation research · 2025Review
- Review
- Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.Science (New York, N.Y.) · 2023Article
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- cFLIPCardiovascular drugs and therapy · 2023Article
- Poziotinib Inhibits HER2-Mutant-Driven Therapeutic Resistance and Multiorgan Metastasis in Breast Cancer.Cancer research · 2022Article
- LINC00355 regulates p27NPJ breast cancer · 2022Article
- Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases.Cell death & disease · 2022Review
- The deubiquitinase Usp27x as a novel regulator of cFLIPApoptosis : an international journal on programmed cell death · 2022Article
- Multiple roles of caspase-8 in cell death, inflammation, and innate immunity.Journal of leukocyte biology · 2021Review
- Protein Kinase-Mediated Decision Between the Life and Death.Advances in experimental medicine and biology · 2021Article
- TNF Is Partially Required for Cell-Death-Triggered Skin Inflammation upon Acute Loss of cFLIP.International journal of molecular sciences · 2020Article
- TNF Signaling Dictates Myeloid and Non-Myeloid Cell Crosstalk to Execute MCMV-Induced Extrinsic Apoptosis.Viruses · 2020Article
- Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression.Nature communications · 2020Article
- Transcription modulation by CDK9 regulates inflammatory genes and RIPK3-MLKL-mediated necroptosis in periodontitis progression.Scientific reports · 2019Article
- Guidelines for evaluating myocardial cell death.American journal of physiology. Heart and circulatory physiology · 2019Review
- The many faces of tumor necrosis factor signaling in the intestinal epithelium.Genes and immunity · 2019Review
- c-FLIP and CD95 signaling are essential for survival of renal cell carcinoma.Cell death & disease · 2019Article
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Death receptors (DRs) induce apoptosis but also stimulate proinflammatory "non-apoptotic" signaling (e.g. NF-κB and mitogen-activated protein kinase (MAPK) activation) and inhibit distinct steps of DR-activated maturation of procaspase-8. To examine whether isoforms of cellular FLIP (cFLIP) or its cleavage products differentially regulate DR signaling, we established HaCaT cells expressing cFLIP(S), cFLIP(L), or mutants of cFLIP(L) (cFLIP(D376N) and cFLIP(p43)). cFLIP variants blocked TRAIL- and CD95L-induced apoptosis, but the cleavage pattern of caspase-8 in the death inducing signaling complex was different: cFLIP(L) induced processing of caspase-8 to the p43/41 fragments irrespective of cFLIP cleavage. cFLIP(S) or cFLIP(p43) blocked procaspase-8 cleavage. Analyzing non-apoptotic signaling pathways, we found that TRAIL and CD95L activate JNK and p38 within 15 min. cFLIP variants and different caspase inhibitors blocked late death ligand-induced JNK or p38 MAPK activation suggesting that these responses are secondary to cell death. cFLIP isoforms/mutants also blocked death ligand-mediated gene induction of CXCL-8 (IL-8). Knockdown of caspase-8 fully suppressed apoptotic and non-apoptotic signaling. Knockdown of cFLIP isoforms in primary human keratinocytes enhanced CD95L- and TRAIL-induced NF-κB activation, and JNK and p38 activation, underscoring the regulatory role of cFLIP for these DR-mediated signals. Whereas the presence of caspase-8 is critical for apoptotic and non-apoptotic signaling, cFLIP isoforms are potent inhibitors of TRAIL- and CD95L-induced apoptosis, NF-κB activation, and the late JNK and p38 MAPK activation. cFLIP-mediated inhibition of CD95 and TRAIL DR could be of crucial importance during keratinocyte skin carcinogenesis and for the activation of innate and/or adaptive immune responses triggered by DR activation in the skin.
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