Gene Symbol: Cflar
Description: CASP8 and FADD-like apoptosis regulator
Alias: Flip, CASP8 and FADD-like apoptosis regulator
Species: rat
Products:     Cflar

Top Publications

  1. Nastiuk K, Kim J, Mann M, Krolewski J. Androgen regulation of FLICE-like inhibitory protein gene expression in the rat prostate. J Cell Physiol. 2003;196:386-93 pubmed
    ..a catalytically inactive cysteinyl aspartate-specific protease (caspase) analog, FLICE-like inhibitor protein (FLIP), decreases during the first day following castration...
  2. Benayoun B, Baghdiguian S, Lajmanovich A, Bartoli M, Daniele N, Gicquel E, et al. NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A. FASEB J. 2008;22:1521-9 pubmed
    ..We first show that the antiapoptotic factor cellular-FLICE inhibitory protein (c-FLIP), which is dependent on the NF-kappaB pathway in normal muscle cells, is down-regulated in LGMD2A biopsies...
  3. Moubarak R, Sole C, Pascual M, Gutierrez H, Llovera M, Perez Garcia M, et al. The death receptor antagonist FLIP-L interacts with Trk and is necessary for neurite outgrowth induced by neurotrophins. J Neurosci. 2010;30:6094-105 pubmed publisher
    FLICE-inhibitory protein (FLIP) is an endogenous inhibitor of the signaling pathway triggered by the activation of death receptors...
  4. Bangert A, Cristofanon S, Eckhardt I, Abhari B, Kolodziej S, Hacker S, et al. Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP. Oncogene. 2012;31:4677-88 pubmed publisher
    ..Thus, these findings demonstrate that HDACI represent a promising strategy to prime glioblastoma for TRAIL-induced apoptosis by targeting cFLIP. ..
  5. Marqués Fernández F, Planells Ferrer L, Gozzelino R, Galenkamp K, Reix S, Llecha Cano N, et al. TNF? induces survival through the FLIP-L-dependent activation of the MAPK/ERK pathway. Cell Death Dis. 2013;4:e493 pubmed publisher
    ..B (NF-?B) to the nucleus and activation of survival-related genes such as FLICE-like inhibitory protein long form (FLIP-L) or IAPs...
  6. Pennarun B, Meijer A, de Vries E, Kleibeuker J, Kruyt F, de Jong S. Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer. Biochim Biophys Acta. 2010;1805:123-40 pubmed publisher
    ..The anti-apoptotic protein FLIP can also be recruited to the DISC to replace caspase 8 and form an inactive complex...
  7. Oberst A, Dillon C, Weinlich R, McCormick L, Fitzgerald P, Pop C, et al. Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature. 2011;471:363-7 pubmed publisher
    ..RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with FLICE-like inhibitory protein long (FLIP(L), also known as CFLAR), and this complex is required for the protective function.
  8. Benesch M, Platzbecker U, Ward J, Deeg H, Leisenring W. Expression of FLIP(Long) and FLIP(Short) in bone marrow mononuclear and CD34+ cells in patients with myelodysplastic syndrome: correlation with apoptosis. Leukemia. 2003;17:2460-6 pubmed
    ..b>FLIP (FLICE (FAS-associated death-domain-like IL-1beta-converting enzyme)-inhibitory protein)) was identified as an ..
  9. McLornan D, Hay J, McLaughlin K, Holohan C, Burnett A, Hills R, et al. Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia. Br J Haematol. 2013;160:188-98 pubmed publisher
    Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti-apoptotic proteins c-FLIP(L) and c-FLIP(S) (..

More Information


  1. Davis A, Lotocki G, Marcillo A, Dietrich W, Keane R. FasL, Fas, and death-inducing signaling complex (DISC) proteins are recruited to membrane rafts after spinal cord injury. J Neurotrauma. 2007;24:823-34 pubmed
    ..microdomains where Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC)...
  2. Siu P, Bryner R, Murlasits Z, Alway S. Response of XIAP, ARC, and FLIP apoptotic suppressors to 8 wk of treadmill running in rat heart and skeletal muscle. J Appl Physiol (1985). 2005;99:204-9 pubmed
    ..XIAP), apoptosis repressor with caspases recruitment domain protein (ARC), and FADD-like inhibitor protein (FLIP) in skeletal and cardiac muscles...
  3. Raclaw K, Heemers H, Kidd E, Dehm S, Tindall D. Induction of FLIP expression by androgens protects prostate cancer cells from TRAIL-mediated apoptosis. Prostate. 2008;68:1696-706 pubmed publisher
    ..The cellular Fas/FasL-associated death domain protein-like inhibitory protein (FLIP) inhibits activation of procaspase-8 by death receptor-mediated signaling at the cell surface...
  4. Golan Gerstl R, Wallach Dayan S, Zisman P, Cardoso W, Goldstein R, Breuer R. Cellular FLICE-like inhibitory protein deviates myofibroblast fas-induced apoptosis toward proliferation during lung fibrosis. Am J Respir Cell Mol Biol. 2012;47:271-9 pubmed publisher
    ..Cellular FLICE-like inhibitory protein (c-FLIP) is a regulator of cell death receptor-induced apoptosis in many cell types...
  5. Falschlehner C, Emmerich C, Gerlach B, Walczak H. TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol. 2007;39:1462-75 pubmed
    ..In this review we intend to summarise the most important findings on the TRAIL signalling network and the interplay in the decisions between life and death of a tumor cell. ..
  6. Vanlangenakker N, Bertrand M, Bogaert P, Vandenabeele P, Vanden Berghe T. TNF-induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II members. Cell Death Dis. 2011;2:e230 pubmed publisher
    ..Finally, we also report RIP1-independent but RIP3-mediated necroptosis in the context of TNF signaling in particular conditions. ..
  7. Gilot D, Serandour A, Ilyin G, Lagadic Gossmann D, Loyer P, Corlu A, et al. A role for caspase-8 and c-FLIPL in proliferation and cell-cycle progression of primary hepatocytes. Carcinogenesis. 2005;26:2086-94 pubmed
    ..In the present study, we investigated if c-FLIP(L) (cellular FLICE-inhibitory protein, long isoform) could be involved in epidermal growth factor (EGF)-stimulated ..
  8. Oh H, Namkoong S, Lee S, Por E, Kim C, Billiar T, et al. Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP. Cell Death Differ. 2006;13:512-23 pubmed
    ..Our results indicate that DEX exerts a protective role in death receptor-induced in vitro and in vivo hepatocyte apoptosis by upregulating cFLIP expression. ..
  9. Yaniv G, Shilkrut M, Lotan R, Berke G, Larisch S, Binah O. Hypoxia predisposes neonatal rat ventricular myocytes to apoptosis induced by activation of the Fas (CD95/Apo-1) receptor: Fas activation and apoptosis in hypoxic myocytes. Cardiovasc Res. 2002;54:611-23 pubmed
    ..ARTS and FADD by 323 and 250%, respectively, and decreased the expression of the antiapoptotic proteins ARC and FLIP by 90 and 60%, respectively...
  10. Bhuiyan M, Takada Y, Shioda N, Moriguchi S, Kasahara J, Fukunaga K. Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein. Cardiovasc Ther. 2008;26:10-23 pubmed publisher
    ..Furthermore, treatment with vanadyl sulfate significantly increased FLICE-inhibitory protein (FLIP) expression, and decreased expression of Fas ligand and Bim in cardiomyocytes...
  11. Gao J, Wang F, Wang W, Su Z, Guo C, Cao S. Emodin suppresses hyperglycemia-induced proliferation and fibronectin expression in mesangial cells via inhibiting cFLIP. PLoS ONE. 2014;9:e93588 pubmed publisher
    ..These findings demonstrate that emodin represent a promising strategy to prevent renal dysfunction in early-stage of diabetes mellitus...
  12. Imanishi T, McBride J, Ho Q, O Brien K, Schwartz S, Han D. Expression of cellular FLICE-inhibitory protein in human coronary arteries and in a rat vascular injury model. Am J Pathol. 2000;156:125-37 pubmed
    ..MRIT, also known as c-FLICE-inhibitory protein (c-FLIP), is an enzymatically inactive homolog of caspase 8 with homology to viral FLIP (v-FLIP)...
  13. Zhang J, Wang Q, Zhu N, Yu M, Shen B, Xiang J, et al. Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIP(L) and MKP-1, thereby antagonizing UV-induced apoptosis. Cell Death Differ. 2008;15:1654-62 pubmed publisher
    ..The induction of the long form of cellular FLICE-inhibitory protein (c-FLIP(L)) and mitogen-activated protein kinase phosphatase-1 (MKP-1), but not DLC and p21(WAF1) by CREB was required for ..
  14. Jarvinen K, Hotti A, Santos L, Nummela P, Hölttä E. Caspase-8, c-FLIP, and caspase-9 in c-Myc-induced apoptosis of fibroblasts. Exp Cell Res. 2011;317:2602-15 pubmed publisher
    ..Interestingly, the expression of cellular FLICE inhibitory protein (c-FLIP) mRNA and the encoded protein, c-FLIP(L), a catalytically inactive homologue of caspase-8, were down-regulated ..
  15. Feoktistova M, Geserick P, Kellert B, Dimitrova D, Langlais C, Hupe M, et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell. 2011;43:449-63 pubmed publisher
    ..The differential quality of cell death mediated by the Ripoptosome may cause important pathophysiological consequences during inflammatory responses. ..
  16. Shen L, Sun Z, Zhao F, Wang W, Zhang W, Zhu H. Expression of c-FLIP in a rat model of sepsis and its effects on endothelial apoptosis. Mol Med Rep. 2017;16:231-237 pubmed publisher
    ..Apoptosis is important in the pathogenesis of sepsis. Cellular FLICE‑inhibitory protein (c‑FLIP) is a catalytically inactive caspase‑8 homologue, which negatively interferes with apoptotic signaling...
  17. Davidson S, Stephanou A, Latchman D. FLIP protects cardiomyocytes from apoptosis induced by simulated ischemia/reoxygenation, as demonstrated by short hairpin-induced (shRNA) silencing of FLIP mRNA. J Mol Cell Cardiol. 2003;35:1359-64 pubmed
    ..FLICE-inhibitory protein (FLIP) is a cellular protein that, in overexpression experiments in other cell types, has been shown to be capable of ..
  18. Strasser A, Jost P, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009;30:180-92 pubmed publisher
    ..This review describes current understanding of Fas-induced apoptosis signaling and proposes experimental strategies for future advances. ..
  19. Jaita G, Zárate S, Ferraris J, Gottardo M, Eijo G, Magri M, et al. Estradiol Upregulates c-FLIPlong Expression in Anterior Pituitary Cells. Horm Metab Res. 2016;48:275-9 pubmed publisher
    ..We have previously shown that estrogens sensitize anterior pituitary cells to pro-apoptotic stimuli. c-FLIP (cellular-FLICE-inhibitory-protein) isoforms are regulatory proteins of apoptosis triggered by death receptors...
  20. Wang L, Azad N, Kongkaneramit L, Chen F, Lu Y, Jiang B, et al. The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation. J Immunol. 2008;180:3072-80 pubmed
    ..has been associated with reactive oxygen species (ROS) generation and down-regulation of FLICE inhibitory protein (FLIP); however, the relationship between these two events and their role in Fas-mediated apoptosis are unclear...
  21. Cudrici C, Niculescu F, Jensen T, Zafranskaia E, Fosbrink M, Rus V, et al. C5b-9 terminal complex protects oligodendrocytes from apoptotic cell death by inhibiting caspase-8 processing and up-regulating FLIP. J Immunol. 2006;176:3173-80 pubmed
    ..caspase-8 processing was increased in association with Bid cleavage and markedly reduced expression of cellular FLIP long isoform protein...
  22. Giampietri C, Petrungaro S, Coluccia P, Antonangeli F, Giannakakis K, Faraggiana T, et al. c-Flip overexpression affects satellite cell proliferation and promotes skeletal muscle aging. Cell Death Dis. 2010;1:e38 pubmed publisher
    This study shows that forcing c-Flip overexpression in undifferentiated skeletal myogenic cells in vivo results in early aging muscle phenotype...
  23. Yin J, Liu F, Gao Y, Liao W. [Hypobaric hypoxia increases the expression of death receptor 5 and inhibits that of FLICE-like inhibitory protein in the rat testis]. Zhonghua Nan Ke Xue. 2013;19:588-92 pubmed
    ..of hypobaric hypoxia on the expressions of death receptor 5 (DR5) and cellular FLICE-like inhibitory protein (c-FLIP) and the distribution of c-FLIP in the rat testis...
  24. Dzietko M, Boos V, Sifringer M, Polley O, Gerstner B, Genz K, et al. A critical role for Fas/CD-95 dependent signaling pathways in the pathogenesis of hyperoxia-induced brain injury. Ann Neurol. 2008;64:664-73 pubmed publisher
    ..domain (FADD), the long and short form of FADD-like interleukin-1beta-converting enzyme (FLICE) inhibitory protein (FLIP-L, FLIP-S), and cleavage of caspase-8 and caspase-3...
  25. Rushworth S, MacEwan D. HO-1 underlies resistance of AML cells to TNF-induced apoptosis. Blood. 2008;111:3793-801 pubmed publisher
    ..These results demonstrate a novel mechanism by which TNF-induced cell death is inhibited in AML cells through the induction of HO-1, via Nrf2 activation. ..
  26. Giampietri C, Petrungaro S, Klinger F, Coluccia P, Paone A, Vivarelli E, et al. c-Flip expression and function in fetal mouse gonocytes. FASEB J. 2006;20:124-6 pubmed
    ..We evaluated the expression and function of c-Flip, an apoptosis inhibitor known to interfere with the proapoptotic Fas-signaling pathway in a variety of cell types, ..
  27. Bhuiyan M, Shibuya M, Shioda N, Moriguchi S, Kasahara J, Iwabuchi Y, et al. Cytoprotective effect of bis(1-oxy-2-pyridinethiolato)oxovanadiun(IV) on myocardial ischemia/reperfusion injury elicits inhibition of Fas ligand and Bim expression and elevation of FLIP expression. Eur J Pharmacol. 2007;571:180-8 pubmed
    ..Furthermore, treatment with VO(OPT) significantly increased FLIP expression, and decreased expression of Fas ligand and Bim in cardiomyocytes...
  28. Tao R, Berkova Z, Wise J, Rezaeian A, Daniluk U, Ao X, et al. PMLRAR? binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo. Blood. 2011;118:3107-18 pubmed publisher
    ..was demonstrated in U937/PR9 cells, human APL cells and transgenic mouse APL cells, in which PMLRAR? recruited c-FLIP(L/S) and excluded procaspase 8 from Fas death signaling complex...
  29. Imanishi T, Murry C, Reinecke H, Hano T, Nishio I, Liles W, et al. Cellular FLIP is expressed in cardiomyocytes and down-regulated in TUNEL-positive grafted cardiac tissues. Cardiovasc Res. 2000;48:101-10 pubmed
    c-FLIP is a natural homologue of caspase 8, and may antagonize activation of death pathways mediated by FADD...
  30. Xiao C, Asselin E, Tsang B. Nuclear factor kappaB-mediated induction of Flice-like inhibitory protein prevents tumor necrosis factor alpha-induced apoptosis in rat granulosa cells. Biol Reprod. 2002;67:436-41 pubmed
    ..of the present studies was to examine the role and regulation of the antiapoptotic Flice-like inhibitory protein (FLIP) in rat granulosa cells by tumor necrosis factor alpha (TNFalpha) in vitro...
  31. Dillon C, Oberst A, Weinlich R, Janke L, Kang T, Ben Moshe T, et al. Survival function of the FADD-CASPASE-8-cFLIP(L) complex. Cell Rep. 2012;1:401-7 pubmed
  32. Wang W, Prince C, Mou Y, Pollman M. Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis. J Biol Chem. 2002;277:21723-9 pubmed
    ..Resistance to FasL-induced apoptosis was associated with the induction of c-FLIP, a primary inhibitor of the FasL signaling pathway...
  33. Shu H, Halpin D, Goeddel D. Casper is a FADD- and caspase-related inducer of apoptosis. Immunity. 1997;6:751-63 pubmed
    ..When overexpressed in mammalian cells, Casper potently induces apoptosis. A C-terminal deletion mutant of Casper inhibits TNF- and Fas-induced cell death, suggesting that Casper is involved in these apoptotic pathways. ..
  34. Bouchet D, Tesson L, Menoret S, Charreau B, Mathieu P, Yagita H, et al. Differential sensitivity of endothelial cells of various species to apoptosis induced by gene transfer of Fas ligand: role of FLIP levels. Mol Med. 2002;8:612-23 pubmed
    ..In human ECs, levels of FLICE/caspase 8-inhibitory protein (FLIP) have been shown to control apoptosis mediated by Fas...
  35. Nastiuk K, Yoo K, Lo K, Su K, Yeung P, Kutaka J, et al. FLICE-like inhibitory protein blocks transforming growth factor beta 1-induced caspase activation and apoptosis in prostate epithelial cells. Mol Cancer Res. 2008;6:231-42 pubmed publisher accompanied by a reduction in the expression of the apical caspase inhibitor FLICE-like inhibitory protein (FLIP)...