ArticleThe EMBO journal2006
An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway.
Article in The EMBO journal, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 91 citations in OpenAlex.
- c-FLIP as a master regulator of immune homeostasis and disease mechanisms.Cell death & disease · 2026Review
- Molecular Cell Biology of Apoptosis in Health and Disease.Advances in experimental medicine and biology · 2025Review
- Regulated cell death in glioma: promising targets for natural small-molecule compounds.Frontiers in oncology · 2024Review
- Regulation of distinct caspase-8 functions in retinal ganglion cells and astroglia in experimental glaucoma.Neurobiology of disease · 2021Article
- MIND bomb 2 prevents RIPK1 kinase activity-dependent and -independent apoptosis through ubiquitylation of cFLIPCommunications biology · 2021Article
- Protein Kinase-Mediated Decision Between the Life and Death.Advances in experimental medicine and biology · 2021Article
- TRAIL of Hope Meeting Resistance in Cancer.Trends in cancer · 2020Review
- FLIP(L): the pseudo-caspase.The FEBS journal · 2020Review
- c-FLIP, a Novel Biomarker for Cancer Prognosis, Immunosuppression, Alzheimer's Disease, Chronic Obstructive Pulmonary Disease (COPD), and a Rationale Therapeutic Target.Biomarkers journal · 2019Article
- MKK7, the essential regulator of JNK signaling involved in cancer cell survival: a newly emerging anticancer therapeutic target.Therapeutic advances in medical oncology · 2019Review
- Subcellular Localization and Activity of the Mitogen-Activated Protein Kinase Kinase 7 (MKK7)Molecular pharmacology · 2019Article
- Association of Increased F4/80Arthritis & rheumatology (Hoboken, N.J.) · 2017Article
- Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production.The Journal of biological chemistry · 2017Article
- KSHV reduces autophagy in THP-1 cells and in differentiating monocytes by decreasing CAST/calpastatin and ATG5 expression.Autophagy · 2016Article
- TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice.Journal of cell science · 2016Article
- FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP.International journal of molecular sciences · 2015Review
- Expression levels of heat shock protein 27 and cellular FLICE-like inhibitory protein in prostate cancer correlate with Gleason score sum and pathologic stage.Korean journal of urology · 2015Article
- Harnessing of Programmed Necrosis for Fighting against Cancers.Biomolecules & therapeutics · 2014Review
- Article
- Novel phosphorylation and ubiquitination sites regulate reactive oxygen species-dependent degradation of anti-apoptotic c-FLIP protein.The Journal of biological chemistry · 2013Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inhibition of NF-kappaB activation increases susceptibility to tumor necrosis factor (TNF)alpha-induced cell death, concurrent with caspases and prolonged c-Jun N-terminal kinase (JNK) activation, and reactive oxygen species (ROS) accumulation. However, the detailed mechanisms are unclear. Here we show that cellular FLICE-inhibitory protein (c-FLIP) is rapidly lost in NF-kappaB activation-deficient, but not wild-type fibroblasts upon TNFalpha stimulation, indicating that NF-kappaB normally maintains the cellular levels of c-FLIP. The ectopic expression of the long form of c-FLIP (c-FLIPL) inhibits TNFalpha-induced prolonged JNK activation and ROS accumulation in NF-kappaB activation-deficient fibroblasts. Conversely, TNFalpha induces prolonged JNK activation and ROS accumulation in c-Flip-/- fibroblasts. Moreover, c-FLIPL directly interacts with a JNK activator, MAP kinase kinase (MKK)7, in a TNFalpha-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFbeta-activated kinase 1. This stimuli-dependent interaction of c-FLIPL with MKK7 might selectively suppress the prolonged phase of JNK activation. Taken that ROS promote JNK activation and activation of the JNK pathway may promote ROS accumulation, c-FLIPL might block this positive feedback loop, thereby suppressing ROS accumulation.
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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.