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Gene Review

Cflar  -  CASP8 and FADD-like apoptosis regulator

Mus musculus

Synonyms: 2310024N18Rik, A430105C05Rik, AI646576, AU021929, CASH, ...
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Disease relevance of Cflar


High impact information on Cflar


Biological context of Cflar


Anatomical context of Cflar


Associations of Cflar with chemical compounds

  • Expression of c-FLIP significantly increased the resistance towards gemcitabine [13].
  • The antiapoptotic effect of bortezomib was likely mediated by an increase in hepatic cellular FLICE inhibitory protein (c-FLIP) levels, a potent antiapoptotic protein [14].
  • Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC [15].
  • We found that c-FLIP promoter contained multiple functional androgen response elements [16].
  • The levels of cellular FLIP (c-FLIP), competitively interacting with caspase-8, were down-regulated by stimulation with IFN-beta but were reversed by the proteasome inhibitor lactacystin [17].

Regulatory relationships of Cflar

  • As a key inhibitor of Fas-mediated apoptosis, we found expression of the cellular FLICE-inhibitory protein (c-FLIP) to be induced by TGF-beta in resting as well as in activated microglia [18].
  • Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-kappaB activation and life/death decisions in lymphocytes and DCs [19].
  • In this regard, caspase-12 seems to be the cFLIP counterpart for regulating the inflammatory branch of the caspase cascade [20].

Other interactions of Cflar

  • In conclusion, both c-FLIP proteins prevent caspase-8 activation at different levels of procaspase-8 processing at the DISC [21].
  • CONCLUSION: This is the first report of c-FLIP regulation by IL-2 in renal TECs [2].
  • Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor-induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process [22].
  • Their survival was associated with expression of antiapoptotic cellular FLICE-inhibitory protein (c-FLIP), Bcl-X(L), and Bcl-2 [23].
  • Retroviral transduction of RelA(-/-) B cells with either cFLIP or Bcl-2 significantly reduced TNF-alpha killing [24].

Analytical, diagnostic and therapeutic context of Cflar


  1. Reduced myocarditis following Coxsackievirus infection in cellular FLICE inhibitory protein--long form-transgenic mice. Huber, S., Dohrman, A., Sartini, D., Budd, R.C. Immunology (2006) [Pubmed]
  2. IL-2-mediated apoptosis of kidney tubular epithelial cells is regulated by the caspase-8 inhibitor c-FLIP. Du, C., Guan, Q., Yin, Z., Zhong, R., Jevnikar, A.M. Kidney Int. (2005) [Pubmed]
  3. Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes. Van Parijs, L., Refaeli, Y., Abbas, A.K., Baltimore, D. Immunity (1999) [Pubmed]
  4. Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression. Ivanov, V.N., Hei, T.K. Exp. Cell Res. (2006) [Pubmed]
  5. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Yeh, W.C., Itie, A., Elia, A.J., Ng, M., Shu, H.B., Wakeham, A., Mirtsos, C., Suzuki, N., Bonnard, M., Goeddel, D.V., Mak, T.W. Immunity (2000) [Pubmed]
  6. c-FLICE inhibitory protein expression inhibits T-cell activation. Tai, T.S., Fang, L.W., Lai, M.Z. Cell Death Differ. (2004) [Pubmed]
  7. Expression of cellular FLICE inhibitory proteins (cFLIP) in normal and traumatic murine and human cerebral cortex. Hainsworth, A.H., Bermpohl, D., Webb, T.E., Darwish, R., Fiskum, G., Qiu, J., McCarthy, D., Moskowitz, M.A., Whalen, M.J. J. Cereb. Blood Flow Metab. (2005) [Pubmed]
  8. Vanishin is a novel ubiquitinylated death-effector domain protein that blocks ERK activation. Sur, R., Ramos, J.W. Biochem. J. (2005) [Pubmed]
  9. Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP. Oh, H.Y., Namkoong, S., Lee, S.J., Por, E., Kim, C.K., Billiar, T.R., Han, J.A., Ha, K.S., Chung, H.T., Kwon, Y.G., Lee, H., Kim, Y.M. Cell Death Differ. (2006) [Pubmed]
  10. Keratins modulate c-Flip/extracellular signal-regulated kinase 1 and 2 antiapoptotic signaling in simple epithelial cells. Gilbert, S., Loranger, A., Marceau, N. Mol. Cell. Biol. (2004) [Pubmed]
  11. Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP. Wang, J., Lobito, A.A., Shen, F., Hornung, F., Winoto, A., Lenardo, M.J. Eur. J. Immunol. (2000) [Pubmed]
  12. c-Flip(L) is expressed in undifferentiated mouse male germ cells. Giampietri, C., Petrungaro, S., Coluccia, P., Antonangeli, F., Paone, A., Padula, F., De Cesaris, P., Ziparo, E., Filippini, A. FEBS Lett. (2006) [Pubmed]
  13. Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis. Schniewind, B., Christgen, M., Kurdow, R., Haye, S., Kremer, B., Kalthoff, H., Ungefroren, H. Int. J. Cancer (2004) [Pubmed]
  14. Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse. Anan, A., Baskin-Bey, E.S., Isomoto, H., Mott, J.L., Bronk, S.F., Albrecht, J.H., Gores, G.J. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  15. Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL. Ganten, T.M., Koschny, R., Haas, T.L., Sykora, J., Li-Weber, M., Herzer, K., Walczak, H. Hepatology (2005) [Pubmed]
  16. The androgen receptor directly targets the cellular Fas/FasL-associated death domain protein-like inhibitory protein gene to promote the androgen-independent growth of prostate cancer cells. Gao, S., Lee, P., Wang, H., Gerald, W., Adler, M., Zhang, L., Wang, Y.F., Wang, Z. Mol. Endocrinol. (2005) [Pubmed]
  17. Interferon-beta-induced activation of c-Jun NH2-terminal kinase mediates apoptosis through up-regulation of CD95 in CH31 B lymphoma cells. Takada, E., Shimo, K., Hata, K., Abiake, M., Mukai, Y., Moriyama, M., Heasley, L., Mizuguchi, J. Exp. Cell Res. (2005) [Pubmed]
  18. TGF-beta induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia. Schlapbach, R., Spanaus, K.S., Malipiero, U., Lens, S., Tasinato, A., Tschopp, J., Fontana, A. Eur. J. Immunol. (2000) [Pubmed]
  19. The c-FLIP-NH2 terminus (p22-FLIP) induces NF-kappaB activation. Golks, A., Brenner, D., Krammer, P.H., Lavrik, I.N. J. Exp. Med. (2006) [Pubmed]
  20. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Saleh, M., Mathison, J.C., Wolinski, M.K., Bensinger, S.J., Fitzgerald, P., Droin, N., Ulevitch, R.J., Green, D.R., Nicholson, D.W. Nature (2006) [Pubmed]
  21. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. Krueger, A., Schmitz, I., Baumann, S., Krammer, P.H., Kirchhoff, S. J. Biol. Chem. (2001) [Pubmed]
  22. Cellular FLICE-inhibitory protein is required for T cell survival and cycling. Chau, H., Wong, V., Chen, N.J., Huang, H.L., Lin, W.J., Mirtsos, C., Elford, A.R., Bonnard, M., Wakeham, A., You-Ten, A.I., Lemmers, B., Salmena, L., Pellegrini, M., Hakem, R., Mak, T.W., Ohashi, P., Yeh, W.C. J. Exp. Med. (2005) [Pubmed]
  23. Responding naive T cells differ in their sensitivity to Fas engagement: early death of many T cells is compensated by costimulation of surviving T cells. Maksimow, M., Santanen, M., Jalkanen, S., Hänninen, A. Blood (2003) [Pubmed]
  24. Regulation of developing B cell survival by RelA-containing NF-kappa B complexes. Prendes, M., Zheng, Y., Beg, A.A. J. Immunol. (2003) [Pubmed]
  25. Cellular FLICE-inhibitory protein: an attractive therapeutic target? Micheau, O. Expert Opin. Ther. Targets (2003) [Pubmed]
  26. Porcine (Sus scrofa) cellular FLICE-like inhibitory protein (cFLIP): molecular cloning and comparison with the human and murine cFLIP. Goto, Y., Matsuda-Minehata, F., Inoue, N., Matsui, T., Maeda, A., Manabe, N. J. Reprod. Dev. (2004) [Pubmed]
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