ArticleProceedings of the National Academy of Sciences of the United States of America2016
Balance between short and long isoforms of cFLIP regulates Fas-mediated apoptosis in vivo.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 45 citations in OpenAlex.
- c-FLIP as a master regulator of immune homeostasis and disease mechanisms.Cell death & disease · 2026Review
- Sustained cancer-relevant alternative RNA splicing events driven by PRMT5 in high-risk neuroblastoma.Molecular oncology · 2025Article
- Raver1 linksProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mef2c Exacerbates Neuron Necroptosis via Modulating Alternative Splicing of Cflar in Ischemic Stroke With Hyperlipidemia.CNS neuroscience & therapeutics · 2024Article
- CD14 is a decision-maker between Fas-mediated death and inflammation.Cell reports · 2024Article
- c-FLIP facilitates ZIKV infection by mediating caspase-8/3-dependent apoptosis.PLoS pathogens · 2024Article
- cFLIP in the molecular regulation of astroglia-driven neuroinflammation in experimental glaucoma.Journal of neuroinflammation · 2024Article
- Quantitative Analysis of Isoform Switching in Cancer.International journal of molecular sciences · 2023Article
- Susceptibility and Permissivity of Zebrafish (Viruses · 2023Article
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- Targeting the Bet-Hedging Strategy with an Inhibitor of Bacterial Efflux Capacity Enhances Antibiotic Efficiency and Ameliorates Bacterial Persistence In Vitro.Microorganisms · 2022Article
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- Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway.Journal for immunotherapy of cancer · 2022Article
- Review
- Variability in porcine microRNA genes and its association with mRNA expression and lipid phenotypes.Genetics, selection, evolution : GSE · 2021Article
- Multiple roles of caspase-8 in cell death, inflammation, and innate immunity.Journal of leukocyte biology · 2021Review
- Skipped Over: Tuning Natural Killer Cells Toward HIV Through Alternative Splicing.AIDS research and human retroviruses · 2020Article
- Cell-Penetrable Peptide-Conjugated FADD Induces Apoptosis and Regulates Inflammatory Signaling in Cancer Cells.International journal of molecular sciences · 2020Article
- Data-Driven Modeling Identifies TIRAP-Independent MyD88 Activation Complex and Myddosome Assembly Strategy in LPS/TLR4 Signaling.International journal of molecular sciences · 2020Article
- cFLIPScience (New York, N.Y.) · 2020Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
cFLIP, an inhibitor of apoptosis, is a crucial regulator of cellular death by apoptosis and necroptosis; its importance in development is exemplified by the embryonic lethality in cFLIP-deficient animals. A homolog of caspase 8 (CASP8), cFLIP exists in two main isoforms: cFLIPL (long) and cFLIPR (short). Although both splice variants regulate death receptor (DR)-induced apoptosis by CASP8, the specific role of each isoform is poorly understood. Here, we report a previously unidentified model of resistance to Fas receptor-mediated liver failure in the wild-derived MSM strain, compared with susceptibility in C57BL/6 (B6) mice. Linkage analysis in F2 intercross (B6 x MSM) progeny identified several MSM loci controlling resistance to Fas-mediated death, including the caspase 8- and FADD-like apoptosis regulator (Cflar) locus encoding cFLIP. Furthermore, we identified a 21-bp insertion in the 3' UTR of the fifth exon of Cflar in MSM that influences differential splicing of cFLIP mRNA. Intriguingly, we observed that MSM liver cells predominantly express the FLIPL variant, in contrast to B6 liver cells, which have higher levels of cFLIPR. In keeping with this finding, genome-wide RNA sequencing revealed a relative abundance of FLIPL transcripts in MSM hepatocytes whereas B6 liver cells had significantly more FLIPR mRNA. Importantly, we show that, in the MSM liver, CASP8 is present exclusively as its cleaved p43 product, bound to cFLIPL. Because of partial enzymatic activity of the heterodimer, it might prevent necroptosis. On the other hand, it prevents cleavage of CASP8 to p10/20 necessary for cleavage of caspase 3 and, thus, apoptosis induction. Therefore, MSM hepatocytes are predisposed for protection from DR-mediated cell death.
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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.