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Gene Review

Fas  -  Fas (TNF receptor superfamily member 6)

Mus musculus

Synonyms: AI196731, APO-1, APO1, APT1, Apo-1 antigen, ...
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Disease relevance of Fas


Psychiatry related information on Fas

  • Stimulation of natural killer T cells during alcohol consumption induces serious liver injury by a mechanism that involves concomitant signals by Fas and tumor necrosis factor receptor-1 on alcohol-stressed hepatocytes [11].
  • ALG-3, a truncated form of the familial Alzheimer's disease gene PS2, confers resistance to TCR- and Fas-induced apoptosis [12].
  • Importantly, re-expression of Fas in these cells results in either the complete abolishment of tumor development, or in a significant extenuation of the latency period of tumor outgrowth [13].
  • These Id/lpr mice provided an ideal system for studying the relationship between the exogenously and endogenously induced responses because: (1) VHIdCR antibodies have been shown to bind autoantigens in vitro; and (2) serological and molecular reagents exist which can identify and monitor VHIdCR antibody production as disease progresses [14].
  • Auditory brainstem response (ABR) audiometry showed normal auditory thresholds in C3H/lpr mice at 4 months of age, but elevated thresholds by 6 months, particularly in the high frequencies [15].

High impact information on Fas

  • The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances [16].
  • Virtually all of the measurable cell-mediated cytotoxicity delivered by cytotoxic T lymphocytes and natural killer cells comes from either the granule exocytosis pathway or the Fas pathway [16].
  • Analyses of mice deficient in perforin and/or Fas demonstrate that cytolysis is critical for immunity against some, but not all, infections and also reveal the contribution of cytolysis to the pathogenesis of disease [17].
  • Most recent evidence suggests that complement also regulates elimination of self-reactive B cells, as breeding of mice that are deficient in C4 or CD21/CD35 with the lupus-prone strain of lpr mice demonstrates an exacerbation of disease due to an increase in autoantibodies [18].
  • So far, evidence for a role of Fas-dependent cytotoxicity as a T cell effector mechanism in vivo is lacking [19].

Chemical compound and disease context of Fas


Biological context of Fas


Anatomical context of Fas

  • Surprisingly, these transgenic mice showed heightened sensitivity to diabetogenic T cells, which was due to self-destruction of beta cells upon T cell-mediated induction of Fas [1].
  • The recombinant gld FasL expressed in COS cells could not induce apoptosis in cells expressing Fas [30].
  • In addition, antibody against Fas prevented vascular tube formation of choroidal endothelial cells derived from the eye in a three-dimensional in vitro assay [2].
  • We demonstrate that blocking the interactions between lymphocyte function associated (LFA)-1 and intercellular adhesion molecule(ICAM)-1 and ICAM-2 completely suppresses Fas-dependent B cell lysis [31].
  • Hepatocytes bear Fas but do not express Bcl-2, a protein that plays, in a number of conditions, a protective role against apoptosis [32].

Associations of Fas with chemical compounds


Physical interactions of Fas


Regulatory relationships of Fas

  • CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly [42].
  • The addition of IFNgamma markedly increased the percentage of cells expressing Fas on the surface of the ECFCs as well as the intensity of Fas expression [43].
  • Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex [44].
  • In contrast, PKB requires de novo gene transcription by NF-kappaB to block apoptosis triggered by the Fas death receptor [45].
  • This conclusion was supported by the following findings: 1) A 24-h treatment with IL-12 plus IL-18 enhanced Fas expression and annexin staining among basophil precursor-enriched lin(-)c-kit(-) splenocytes [46].
  • Knocking down FLIP expression abolishes the ability of Met to inhibit Fas-triggered hepatocyte death, demonstrating the functional requirement of FLIP in HGF anti-apoptotic signals [47].
  • Beta-catenin bound to and stimulated the Fas promoter [48].

Other interactions of Fas

  • Mice homozygous for lpr (lymphoproliferation) or gld (generalized lymphoproliferative disease) develop lymphadenopathy and suffer from autoimmune disease [30].
  • Other proteins, notably Daxx, also bind Fas and presumably mediate a FADD-independent apoptotic pathway [26].
  • In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease [49].
  • Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice [50].
  • CONCLUSIONS: NO protects hepatocytes from TNF-alpha- and Fas-mediated apoptosis [35].
  • Further, mice (Bcl2l11(-/-)Fas(lpr/lpr)) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11(-/-)) and and with an lpr mutation in the gene encoding Fas (Fas(lpr/lpr)) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11(-/-) or Fas(lpr/lpr) mice [51].

Analytical, diagnostic and therapeutic context of Fas

  • The nonapoptotic functions of Fas ligation are incompletely characterized [52].
  • In contrast to expectations, we show here that Fas-deficient mice developed less-severe collagen-induced arthritis than did control mice [52].
  • Fas-mediated apoptosis, induced when a Fas monoclonal antibody bound to and activated the Fas receptor on these cells, was assessed morphologically and by flow cytometry [53].
  • Levels of proteins involved in Fas-mediated apoptosis and cleavage of poly(adenosine diphosphate-ribose) polymerase (PARP), an end product of caspase activation, were determined by immunoblotting [53].
  • Only a small percentage of normal human ECFCs express Fas and this is present at a low level as detected by Northern blotting for the Fas mRNA and flow cytometric analysis of Fas protein using a specific mouse monoclonal antibody [43].


  1. The role of Fas in autoimmune diabetes. Chervonsky, A.V., Wang, Y., Wong, F.S., Visintin, I., Flavell, R.A., Janeway, C.A., Matis, L.A. Cell (1997) [Pubmed]
  2. Fas ligand (CD95 ligand) controls angiogenesis beneath the retina. Kaplan, H.J., Leibole, M.A., Tezel, T., Ferguson, T.A. Nat. Med. (1999) [Pubmed]
  3. Dual role for Fas ligand in the initiation of and recovery from experimental allergic encephalomyelitis. Sabelko-Downes, K.A., Cross, A.H., Russell, J.H. J. Exp. Med. (1999) [Pubmed]
  4. Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. Zhang, H., Yang, Y., Horton, J.L., Samoilova, E.B., Judge, T.A., Turka, L.A., Wilson, J.M., Chen, Y. J. Clin. Invest. (1997) [Pubmed]
  5. Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. Kuwano, K., Hagimoto, N., Kawasaki, M., Yatomi, T., Nakamura, N., Nagata, S., Suda, T., Kunitake, R., Maeyama, T., Miyazaki, H., Hara, N. J. Clin. Invest. (1999) [Pubmed]
  6. IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression. Yang, D., Thangaraju, M., Browning, D.D., Dong, Z., Korchin, B., Lev, D.C., Ganapathy, V., Liu, K. J. Immunol. (2007) [Pubmed]
  7. K1 protein of human herpesvirus 8 suppresses lymphoma cell Fas-mediated apoptosis. Wang, S., Wang, S., Maeng, H., Young, D.P., Prakash, O., Fayad, L.E., Younes, A., Samaniego, F. Blood (2007) [Pubmed]
  8. Transient local depletion of Foxp3+ regulatory T cells during recovery from colitis via Fas/Fas ligand-induced death. Reardon, C., Wang, A., McKay, D.M. J. Immunol. (2008) [Pubmed]
  9. Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Hughes, P.D., Belz, G.T., Fortner, K.A., Budd, R.C., Strasser, A., Bouillet, P. Immunity (2008) [Pubmed]
  10. CD95 is a key mediator of invasion and accelerated outgrowth of mouse colorectal liver metastases following radiofrequency ablation. Nijkamp, M.W., Hoogwater, F.J., Steller, E.J., Westendorp, B.F., van der Meulen, T.A., Leenders, M.W., Borel Rinkes, I.H., Kranenburg, O. J. Hepatol. (2010) [Pubmed]
  11. Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption. Minagawa, M., Deng, Q., Liu, Z.X., Tsukamoto, H., Dennert, G. Gastroenterology (2004) [Pubmed]
  12. Dissociation of apoptosis and activation of IL-1beta-converting enzyme/Ced-3 proteases by ALG-2 and the truncated Alzheimer's gene ALG-3. Lacanà, E., Ganjei, J.K., Vito, P., D'Adamio, L. J. Immunol. (1997) [Pubmed]
  13. Fas-dependent tissue turnover is implicated in tumor cell clearance. Schröter, M., Peli, J., Hahne, M., Tschopp, J., Reichmann, E. Oncogene (2000) [Pubmed]
  14. Lack of connectivity between the induced and autoimmune repertoires of lpr/lpr mice. Very, D.L., Panka, D.J., Weissman, D., Wysocki, L., Manser, T., Marshak-Rothstein, A. Immunology (1993) [Pubmed]
  15. Decreased auditory function in the C3H/lpr autoimmune disease mouse. Trune, D.R., Kempton, J.B., Mitchell, C. Hear. Res. (1996) [Pubmed]
  16. Lymphocyte-mediated cytotoxicity. Russell, J.H., Ley, T.J. Annu. Rev. Immunol. (2002) [Pubmed]
  17. CD8+ T cell effector mechanisms in resistance to infection. Harty, J.T., Tvinnereim, A.R., White, D.W. Annu. Rev. Immunol. (2000) [Pubmed]
  18. The role of complement and complement receptors in induction and regulation of immunity. Carroll, M.C. Annu. Rev. Immunol. (1998) [Pubmed]
  19. Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. Kägi, D., Ledermann, B., Bürki, K., Zinkernagel, R.M., Hengartner, H. Annu. Rev. Immunol. (1996) [Pubmed]
  20. Increased mucosal B-lymphocyte apoptosis during polymicrobial sepsis is a Fas ligand but not an endotoxin-mediated process. Ayala, A., Xin Xu, Y., Ayala, C.A., Sonefeld, D.E., Karr, S.M., Evans, T.A., Chaudry, I.H. Blood (1998) [Pubmed]
  21. Apoptosis in adult mouse testis induced by experimental cryptorchidism. Ohta, Y., Nishikawa, A., Fukazawa, Y., Urushitani, H., Matsuzawa, A., Nishina, Y., Iguchi, T. Acta anatomica. (1996) [Pubmed]
  22. The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice. Aoshiba, K., Yasui, S., Tamaoki, J., Nagai, A. Am. J. Respir. Crit. Care Med. (2000) [Pubmed]
  23. 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]
  24. Effects of dietary omega3 and omega6 lipids and vitamin E on proliferative response, lymphoid cell subsets, production of cytokines by spleen cells, and splenic protein levels for cytokines and oncogenes in MRL/MpJ-lpr/lpr mice. Venkatraman, J.T., Chu, W.C. J. Nutr. Biochem. (1999) [Pubmed]
  25. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Yang, X., Khosravi-Far, R., Chang, H.Y., Baltimore, D. Cell (1997) [Pubmed]
  26. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Zhang, J., Cado, D., Chen, A., Kabra, N.H., Winoto, A. Nature (1998) [Pubmed]
  27. Massive upregulation of the Fas ligand in lpr and gld mice: implications for Fas regulation and the graft-versus-host disease-like wasting syndrome. Chu, J.L., Ramos, P., Rosendorff, A., Nikolić-Zugić, J., Lacy, E., Matsuzawa, A., Elkon, K.B. J. Exp. Med. (1995) [Pubmed]
  28. Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity. Lawson, B.R., Baccala, R., Song, J., Croft, M., Kono, D.H., Theofilopoulos, A.N. J. Exp. Med. (2004) [Pubmed]
  29. FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits fas-mediated Jun NH(2)-terminal kinase activation. Rochat-Steiner, V., Becker, K., Micheau, O., Schneider, P., Burns, K., Tschopp, J. J. Exp. Med. (2000) [Pubmed]
  30. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Takahashi, T., Tanaka, M., Brannan, C.I., Jenkins, N.A., Copeland, N.G., Suda, T., Nagata, S. Cell (1994) [Pubmed]
  31. Essential lymphocyte function associated 1 (LFA-1): intercellular adhesion molecule interactions for T cell-mediated B cell apoptosis by Fas/APO-1/CD95. Wang, J., Lenardo, M.J. J. Exp. Med. (1997) [Pubmed]
  32. A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection. Rodriguez, I., Matsuura, K., Khatib, K., Reed, J.C., Nagata, S., Vassalli, P. J. Exp. Med. (1996) [Pubmed]
  33. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Kuida, K., Lippke, J.A., Ku, G., Harding, M.W., Livingston, D.J., Su, M.S., Flavell, R.A. Science (1995) [Pubmed]
  34. Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy. Nakashima, H., Inui, T., Habu, Y., Kinoshita, M., Nagao, S., Kawaguchi, A., Miura, S., Shinomiya, N., Yagita, H., Seki, S. Gastroenterology (2006) [Pubmed]
  35. NF-kappaB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis. Hatano, E., Bennett, B.L., Manning, A.M., Qian, T., Lemasters, J.J., Brenner, D.A. Gastroenterology (2001) [Pubmed]
  36. LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level. Ducoroy, P., Micheau, O., Perruche, S., Dubrez-Daloz, L., de Fornel, D., Dutartre, P., Saas, P., Solary, E. Blood (2003) [Pubmed]
  37. Ceramide-induced cell death is independent of the Fas/Fas ligand pathway and is prevented by Nur77 overexpression in A20 B cells. Brás, A., Albar, J.P., Leonardo, E., de Buitrago, G.G., Martínez-A, C. Cell Death Differ. (2000) [Pubmed]
  38. The cardiac Fas (APO-1/CD95) Receptor/Fas ligand system : relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes. Wollert, K.C., Heineke, J., Westermann, J., Lüdde, M., Fiedler, B., Zierhut, W., Laurent, D., Bauer, M.K., Schulze-Osthoff, K., Drexler, H. Circulation (2000) [Pubmed]
  39. CD4(+) T-cell-mediated mechanisms of corneal allograft rejection: role of Fas-induced apoptosis. Hegde, S., Beauregard, C., Mayhew, E., Niederkorn, J.Y. Transplantation (2005) [Pubmed]
  40. TNF-alpha and IFN-gamma regulate expression and function of the Fas system in the seminiferous epithelium. Riccioli, A., Starace, D., D'Alessio, A., Starace, G., Padula, F., De Cesaris, P., Filippini, A., Ziparo, E. J. Immunol. (2000) [Pubmed]
  41. Activation of Src-family tyrosine kinases during Fas-induced apoptosis. Schlottmann, K.E., Gulbins, E., Lau, S.M., Coggeshall, K.M. J. Leukoc. Biol. (1996) [Pubmed]
  42. CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. Jones, R.G., Elford, A.R., Parsons, M.J., Wu, L., Krawczyk, C.M., Yeh, W.C., Hakem, R., Rottapel, R., Woodgett, J.R., Ohashi, P.S. J. Exp. Med. (2002) [Pubmed]
  43. Fas ligand is present in human erythroid colony-forming cells and interacts with Fas induced by interferon gamma to produce erythroid cell apoptosis. Dai, C.H., Price, J.O., Brunner, T., Krantz, S.B. Blood (1998) [Pubmed]
  44. 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]
  45. NF-kappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo. Jones, R.G., Saibil, S.D., Pun, J.M., Elford, A.R., Bonnard, M., Pellegrini, M., Arya, S., Parsons, M.E., Krawczyk, C.M., Gerondakis, S., Yeh, W.C., Woodgett, J.R., Boothby, M.R., Ohashi, P.S. J. Immunol. (2005) [Pubmed]
  46. Pro-Th1 cytokines promote Fas-dependent apoptosis of immature peripheral basophils. Schneider, E., Tonanny, M.B., Lisbonne, M., Leite-de-Moraes, M., Dy, M. J. Immunol. (2004) [Pubmed]
  47. Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner. Moumen, A., Ieraci, A., Patané, S., Solé, C., Comella, J.X., Dono, R., Maina, F. Hepatology (2007) [Pubmed]
  48. Stabilized beta-catenin potentiates Fas-mediated T cell apoptosis. Huang, Z., Wang, R., Xie, H., Shang, W., Manicassamy, S., Sun, Z. J. Immunol. (2008) [Pubmed]
  49. A critical role for complement in maintenance of self-tolerance. Prodeus, A.P., Goerg, S., Shen, L.M., Pozdnyakova, O.O., Chu, L., Alicot, E.M., Goodnow, C.C., Carroll, M.C. Immunity (1998) [Pubmed]
  50. Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. Balomenos, D., Rumold, R., Theofilopoulos, A.N. J. Clin. Invest. (1998) [Pubmed]
  51. Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Hutcheson, J., Scatizzi, J.C., Siddiqui, A.M., Haines, G.K., Wu, T., Li, Q.Z., Davis, L.S., Mohan, C., Perlman, H. Immunity (2008) [Pubmed]
  52. Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation. Ma, Y., Liu, H., Tu-Rapp, H., Thiesen, H.J., Ibrahim, S.M., Cole, S.M., Pope, R.M. Nat. Immunol. (2004) [Pubmed]
  53. Progressive resistance to apoptosis in a cell lineage model of human proliferative breast disease. Starcevic, S.L., Elferink, C., Novak, R.F. J. Natl. Cancer Inst. (2001) [Pubmed]
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