Alternative titles; symbols
HGNC Approved Gene Symbol: FASLG
Cytogenetic location: 1q24.3 Genomic coordinates (GRCh38): 1:172,659,103-172,666,876 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.3 | {Lung cancer, susceptibility to} | 211980 | Autosomal dominant; Somatic mutation | 3 |
| Autoimmune lymphoproliferative syndrome, type IB | 601859 | Autosomal dominant | 3 |
Life requires death. Elimination of unwanted cells is vital for embryogenesis, metamorphosis and tissue turnover, as well as for the development and function of the immune system. Mammalian development is tightly regulated not only by the proliferation and differentiation of cells but also by cell death. The cell death that occurs during development or tissue turnover is called programmed cell death, most of which proceeds via apoptosis. Apoptosis is morphologically distinguished from necrosis, which occurs during the accidental cell death caused by physical or chemical agents. During apoptosis, the cytoplasm of the affected cells condenses, and the nucleus also condenses and becomes fragmented. At the final stage of apoptosis, the cells themselves are fragmented (apoptotic bodies) and are phagocytosed by neighboring macrophages and granulocytes. Apoptosis occurs not only during programmed cell death, but also during the death process induced by some cytotoxic T cells. Suda et al. (1993) identified the ligand that triggers cell death by binding to the cell surface receptor variously known as FAS or APT1 (TNFRSF6; 134637). This cell surface receptor was discovered in 1989 with the isolation of 2 monoclonal antibodies (anti-Fas and anti-Apo-1) that had the startling property of killing a human cell line used as the immunogen. Cell death occurred by apoptosis. Cloning of the genes revealed that the antigens recognized by the 2 monoclonal antibodies were one and the same. It is a transmembrane protein related to a family of receptors that includes the 2 tumor necrosis factor (TNF) receptors (191190, 191191). In mice, mutations at the lpr (lymphoproliferation) locus have a defect in the FAS antigen. The inability of homozygous mutant mice to mediate FAS-induced apoptosis provokes a complex immunologic disorder featuring defects in both the B and T lymphoid compartments. A very similar phenotype of mice homozygous for the gld (generalized lymphoproliferative disease) mutation suggested that the gld gene encodes the ligand for FAS. Suda et al. (1993) isolated the ligand from a cytotoxic T hybridoma by a sensitive expression cloning strategy. The amino acid sequence indicated that FAS ligand is a type II transmembrane protein that belongs to the tumor necrosis factor family. Northern hybridization revealed that the ligand is expressed in activated splenocytes and thymocytes, consistent with its involvement in T cell-mediated cytotoxicity, and in several nonlymphoid tissues, such as testis. The FAS antigen is expressed not only in the cells of the immune system but also in the liver, lung, ovary, and heart, where its function was unclear.
Takahashi et al. (1994) isolated the chromosomal gene for human FasL. The human FASL cDNA predicted a type II membrane protein consisting of 281 amino acids and a calculated M(r) of 31,759 that showed 76.9% amino acid sequence identity with the mouse protein. When expressed in COS cells, both human and mouse recombinant FasL induced apoptosis, indicating crossreactivity. A sequence of approximately 300 bp upstream of the ATG initiation codon was found to be highly conserved between mouse and human. Several transcription cis-regulatory elements such as SP1 (189906), NF-kappa-B (see 164011), and IRF1 (147575) were recognized in this region.
Takahashi et al. (1994) determined that the human FASL gene consists of approximately 8 kb and is split into 4 exons.
By interspecific backcross analysis, Takahashi et al. (1994) localized the murine Fasl gene to the same region of mouse chromosome 1 as that occupied by the gld gene.
Takahashi et al. (1994) mapped the human FASL gene to chromosome 1q23 by fluorescence in situ hybridization.
Takahashi et al. (1994) isolated the murine Fasl gene and showed that activated splenocytes from 'generalized lymphoproliferative disease' (gld) mice express Fasl mRNA. However, the Fas ligand protein in gld mice carried a point mutation in the C-terminal region, which is highly conserved among members of the TNF family. Recombinant gld Fas ligand expressed in COS cells could not induce apoptosis in cells expressing Fas.
Testis is a remarkably immune-privileged site, long known for its ability to support allogeneic and xenogeneic tissue transplants. Bellgrau et al. (1995) reported results suggesting that expression of FasL by Sertoli cells accounts for the immune-privileged nature of testis. Testis grafts derived from mice that can express functional FasL survived indefinitely when transplanted under the kidney capsule of allogeneic mice, whereas testis graft derived from mutant gld mice, which express nonfunctional ligand, were rejected. The authors speculated that FasL expression in the testis probably acts by inducing apoptotic cell death of Fas-expressing, recipient T cells activated in response to graft antigens. D'Alessio et al. (2001) demonstrated that the attribution of testicular expression of FasL to Sertoli cells is erroneous and that FasL transcription instead occurs in meiotic and postmeiotic germ cells, whereas the protein is only displayed on mature spermatozoa. These findings point to a significant role of the Fas system in the biology of mammalian reproduction.
Hahne et al. (1996) stated that, despite the existence of melanoma-specific cytolytic T cells in tumor-infiltrating lymphocytes and in peripheral blood from melanoma patients, and the definition of 12 CTL-defined melanoma peptide antigens, melanoma cells are able to avoid immune detection in most instances. The investigators proposed that FASL-expressing melanoma cells may kill FAS (134637)-sensitive activating T lymphocytes. They analyzed FASL expression in melanoma cells and demonstrated substantial quantities of FASL in lysates of a series of human melanoma cells. Two molecular species were identified: a 40-kD membrane-bound FASL and a 27-kD extracellular FASL. Hahne et al. (1996) also demonstrated that the majority of cells infiltrating the tumors were FAS-positive. No FASL was found in normal melanocytes of the skin, suggesting that FASL upregulation occurs during tumorigenesis. Hahne et al. (1996) proposed that FASL-expressing melanoma cells might induce apoptosis of FAS-sensitive tumor infiltrating cells. They reported that injection of FasL+ mouse melanoma cells in mice led to rapid tumor formation. When FasL+ mouse melanoma cells were injected into FAS-deficient mutant mice, tumorigenesis was delayed. These findings led Hahne et al. (1996) to conclude that FASL may contribute to the immune privilege of tumors. They proposed further that pharmacologic products that render infiltrating T cells insensitive to FASL-induced killing may break the immunologic unresponsiveness to melanoma and provide a complementary approach in the therapy of malignant melanoma.
In the United States more than 43,000 corneal transplants are performed each year, making it the most common form of solid tissue transplantation, and second only to bone marrow transplants in overall numbers performed. Corneal transplantation is also one of the most successful types of transplantation with failure rates at only 10 to 15% after 1 year and approximately 30% after 5 years. Stuart et al. (1997) demonstrated that the very high percentage of successful corneal transplants, without tissue matching or immunosuppressant therapy, is related to the expression of abundant functional FASL in the cornea, capable of killing FASL(+) lymphoid cells. Using a mouse model for corneal allograft transplantation, FasL(+) orthografts were accepted at a rate of 45%, whereas FasL(-) or normal grafts transplanted to Fas(-) mice were rejected 100% of the time.
Viard et al. (1998) detected high levels of soluble FASL in the sera of patients with toxic epidermal necrolysis (TEN; 608579). Keratinocytes of TEN patients produced FASL, which induced keratinic apoptosis. Incubating keratinocytes with intravenous immunoglobulin (IVIG) completely inhibited FAS-mediated keratinocyte apoptosis. A naturally occurring anti-FAS immunoglobulin present in IVIG blocks the FAS receptor and mediates this response. Ten patients with TEN were treated with IVIG. Progression of skin disease was rapidly reversed in all cases.
DNA-damaged cells can either repair the DNA or be eliminated through a homeostatic control mechanism mediated by p53 (191170) termed 'cellular proofreading.' Elimination of DNA-damaged cells after UV radiation through sunburn cell (or apoptotic keratinocyte) formation is thought to be pivotal for the removal of precancerous skin cells. Hill et al. (1999) demonstrated that sunburn cell formation is dependent upon FasL. Chronic exposure to UV radiation caused 14 of 20, or 70%, of FasL-deficient mice and 1 of 20, or 5%, of wildtype mice to accumulate p53 mutations in the epidermis. Hill et al. (1999) concluded that FASL-mediated apoptosis is important for skin homeostasis, suggesting that the dysregulation of FAS-FASL interactions may be central to the development of skin cancer.
Pestano et al. (1999) identified a differentiative pathway taken by CD8 cells bearing receptors that cannot engage class I MHC (see 142800) self-peptide molecules because of incorrect thymic selection, defects in peripheral MHC class I expression, or antigen presentation. In any of these cases, failed CD8 T-cell receptor coengagement results in downregulation of genes that account for specialized cytolytic T-lymphocyte function and resistance to cell death (CD8-alpha/beta, see 186730; granzyme B, 123910; and LKLF, 602016), and upregulation of Fas and FasL death genes. Thus, MHC engagement is required to inhibit expression and delivery of a death program rather than to supply a putative trophic factor for T cell survival. Pestano et al. (1999) hypothesized that defects in delivery of the death signal to these cells underlie the explosive growth and accumulation of double-negative T cells in animals bearing Fas and FasL mutations, in patients that carry inherited mutations of these genes, and in about 25% of systemic lupus erythematosus patients that display the cellular signature of defects in this mechanism of quality control of CD8 cells.
Grassme et al. (2000) showed that Pseudomonas aeruginosa infection induces apoptosis of lung epithelial cells by activation of the endogenous CD95/CD95L system. Deficiency of CD95 or CD95L on epithelial cells prevented apoptosis of lung epithelial cells in vivo as well as in vitro. The importance of CD95/CD95L-mediated lung epithelial cell apoptosis was demonstrated by the rapid development of sepsis in mice deficient in either CD95 or CD95L, but not in normal mice, after P. aeruginosa infection.
Cytomegalovirus (CMV) is a persistent viral pathogen that resides in monocyte/macrophages and dendritic cells (DCs), critical antigen-presenting cells in the immune system. In fetal and compromised immune systems, CMV can be fatal. Raftery et al. (2001) found that recent CMV isolates, but not fibroblast-adapted CMV strains, could infect mature DCs with no change in some cell surface markers. On the other hand, flow cytometric analysis indicated a slight upregulation of the costimulatory molecules CD40 (109535), CD80 (112203), and CD86 (601020), as well as a downregulation of MHC class I and class II molecules. Functional analysis showed that CMV-infected mature DCs suppress T-cell proliferation. Further FACS analysis demonstrated an upregulation of TRAIL (603598) and FASL, molecules that induce T-cell apoptosis through caspase (see CASP8; 601763)-dependent mechanisms, on DCs. Raftery et al. (2001) concluded that CMV evades the immune response by first downregulating MHC antigens, thereby diminishing T-cell responses, followed by an upregulation of apoptosis-inducing ligands that delete activated T cells. They also proposed that nondeletional, possibly cytokine-mediated mechanisms are involved in T-cell suppression.
Using GST pull-down analysis, Ghadimi et al. (2002) showed that the C-terminal SH3 domains of GRB2 (108355), FBP17 (606191), and PACSIN2 (604960), as well as other related proteins, bind to the polyproline-rich region of the cytoplasmic tail of FASL.
Natural inhibitors of angiogenesis are able to block pathologic neovascularization without harming the preexisting vasculature. Volpert et al. (2002) demonstrated that 2 such inhibitors, thrombospondin I (188060) and pigment epithelium-derived factor (172860), derive specificity for remodeling vessels from their dependence on Fas/FasL-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The antiangiogenic activity of thrombospondin I and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. Volpert et al. (2002) concluded that this example of cooperation between pro- and antiangiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction.
By quantitative immunostaining, Asanuma et al. (2004) found a correlation between expression of survivin (BIRC5; 603352) and FASL in colon cancer tissues. Transfection of survivin into a colon cancer cell line upregulated FASL expression and increased cytotoxicity against a FAS-sensitive T-cell line. Transfected cells showed increased DNA binding of the transcription factor SP1 (189906) to the FASL promoter and upregulation of SP1 phosphorylation at ser and thr residues; the total amount of SP1 was not changed. Inhibition of survivin expression in a colon cancer cell line by small interfering RNA downregulated FASL expression. Asanuma et al. (2004) concluded that survivin enables cancer cells not only to suppress immune cell attack by inhibiting FAS-mediated apoptosis, but also to attack immune cells by induction of FASL.
Raoul et al. (2006) reported that exogenous NO triggered expression of FASL in cultured motoneurons. In motoneurons from ALS (105400) model mice with mutations in the SOD1 gene (147450), this upregulation resulted in activation of Fas (134637), leading through Daxx (603186) and p38 (MAPK14; 600289) to further NO synthesis. The authors suggested that chronic low-activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS.
Using flow cytometric analysis, Herbeuval et al. (2006) found that human immunodeficiency virus (HIV)-positive patients had reduced circulating CD123 (308385)-positive plasmacytoid DCs in blood compared with HIV-negative controls. However, HIV-positive patients had higher secretion of IFNA (147660), higher cytoplasmic expression of MYD88 (602170) and IRF7 (605047), and higher surface expression of CCR7 (600242), suggesting migration of plasmacytoid DCs to lymph nodes. Immunohistochemical analysis showed high IFNA expression in T cell-rich areas of lymphoid tonsillar tissue of HIV-positive patients. RT-PCR analysis showed that expression of TRAIL and FASL, as well as that of their receptors, was significantly higher in lymphoid tonsillar tissue of patients with progressive HIV disease compared with patients with nonprogressive disease and HIV-negative controls, and TRAIL expression correlated with plasma viral load. Herbeuval et al. (2006) concluded that the TRAIL and FASL apoptotic pathways are activated in more advanced HIV disease.
Nakamura et al. (2007) conditionally deleted estrogen receptor-1 (ESR1; 133430) in adult mouse osteoclasts and showed that the protective effect of estrogen on bone in females involved upregulation of Fasl in osteoclasts of trabecular bone. They concluded that estrogen regulates the life span of mature osteoclasts via induction of the FAS/FASL system.
Villa-Morales et al. (2007) found that expression of Fasl increased early in 2 mouse strains after gamma irradiation and was maintained at high levels for a long time in the strain that resisted tumor development. However, Fasl expression was practically absent in T-cell lymphoblastic lymphomas. Villa-Morales et al. (2007) identified functional polymorphisms in the Fasl promoter between the 2 mouse strains exhibiting distinct levels of Fasl expression and tumor susceptibility. In addition, several functional nucleotide changes in the coding sequences of both Fas and Fasl significantly affected their biologic activities. Villa-Morales et al. (2007) concluded that polymorphisms affecting either the expression or biologic activities of FAS or FASL may contribute to the genetic risk of developing T-cell lymphoblastic lymphomas.
The pathogenesis of systemic lupus erythematosus (SLE; 152700) is multifactorial and polygenic. The apoptosis genes FAS and FASL are candidate contributory genes in SLE, as mutations of these genes result in autoimmunity in several murine models of SLE. In humans, FAS mutations result in autoimmune lymphoproliferative syndrome, or ALPS (e.g., 134637.0001). Wu et al. (1996) screened DNA from 75 patients with SLE by SSCP analysis for potential mutations of the extracellular domain of FASL. A heterozygous SSCP anomaly for FASL was identified in 1 SLE patient who exhibited lymphoadenopathy. Molecular cloning and sequencing indicated that the genomic DNA of this patient contained a heterozygous 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion (134638.0001). A study of peripheral blood mononuclear cells from this patient revealed decreased FASL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation. Lenardo (1999) expressed the opinion that although this patient satisfied the rheumatologic criteria for a diagnosis of SLE, the features were more consistent with ALPS. This might be referred to as ALPS2 or ALPS1B, the form caused by mutations in the FAS gene being designated ALPS1A.
Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer (211980) patients and 1,270 controls for 2 functional polymorphisms in the promoter regions of the FAS and FASL genes, -1377G-A (134637.0021) and -844T-C (134638.0002), respectively. Compared to noncarriers, there was an increased risk of developing lung cancer for carriers of either the FAS -1377AA or the FASL -844CC genotype; carriers of both homozygous genotypes had a more than 4-fold increased risk. Zhang et al. (2005) stated that these results support the hypothesis that the FAS- and FASL-triggered apoptosis pathway plays an important role in human carcinogenesis.
Sun et al. (2005) found that the FAS variants -670A and -1377G and the FASL variant -844T were expressed more highly on stimulated T cells than were the FAS -670G and -1377A variants or the FASL -844C variant. T cells carrying the FASL -844C allele exhibited increased activation-induced cell death. A case-control study of Han Chinese women in Beijing showed a statistically significant 3-fold increased risk of cervical cancer in FASL -844CC homozygotes compared with -844TT homozygotes. A trend for somewhat increased susceptibility in -844CT heterozygotes was not statistically significant. Sun et al. (2005) proposed that polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, possibly caused by tumor cells escaping effector T cells due to enhanced activation-induced cell death.
Mice instilled with silica develop severe pulmonary inflammation with local production of TNFA and interstitial neutrophil and macrophage infiltration in the lungs, a phenotype that resembles silicosis, an industrial era disease that afflicts certain mining professions. Borges et al. (2001) found that Fasl-deficient gld mice had reduced neutrophil extravasation into the bronchoalveolar space, did not show TNFA production increases, and did not have pulmonary inflammation in response to silica. Silica induced deferoxamine-inhibitable Fasl expression in wildtype lung macrophages in vivo and in vitro, as well as apoptosis of pulmonary macrophages. Analysis of bone marrow chimeras and local adoptive transfer experiments demonstrated that wildtype but not Fasl-deficient lung macrophages recruited neutrophils and initiated silicosis. The induction of silicosis could be blocked by the administration of neutralizing anti-Fasl antibodies. Borges et al. (2001) proposed that apoptotic cell death is required for neutrophil extravasation and pulmonary inflammation.
In mice with induced spinal cord injury, Demjen et al. (2004) found that antibody neutralization of CD95 ligand, but not of TNF, significantly decreased apoptotic cell death in the spinal cord as indicated by increased survival of oligodendrocytes, increased markers of axonal growth, and a corresponding increase in locomotor performance.
Ma et al. (2004) observed that Fas-deficient (lpr/lpr) mice had less severe collagen-induced arthritis, but higher levels of Il1b (147720) in joints, than control mice, suggesting inefficient activation through Il1r1 (147810). Fas- and Fasl-deficient mouse macrophages and human macrophages treated with an antagonistic FASL antibody had suppressed NFKB (see 164011) activation and cytokine production in response to IL1B or lipopolysaccharide. Ectopic expression of FADD (602457) or dominant-negative FADD (containing the death domain only) suppressed MYD88 (602170)-induced NFKB and IL6 (147620) promoter activation and cytokine expression. Ma et al. (2004) concluded that the FAS-FASL interaction enhances activation through the IL1R1 or TLR4 (603030) pathway, possibly contributing to the pathogenesis of chronic arthritis.
Karray et al. (2004) used Cre-loxP technology to conditionally induce Fasl-deficient mice. Fasl -/- mice showed normal fecundity, but they developed splenomegaly and lymphadenopathy with lymphocytic infiltration into multiple organs and autoimmune disease in an age-dependent manner. The splenomegaly and lymphadenopathy of Fasl -/- mice were accelerated and more pronounced than in gld mice. More than 50% of Fasl -/- mice died by 4 months of age. Killing of Fas-transfected target cells by Fasl -/- splenocytes was significantly lower than that mediated by gld mice, which were also severely impaired in this function. Karray et al. (2004) proposed that the Fasl allele of gld mice may encode a protein still able to bind, albeit weakly, to the Fas receptor.
O'Reilly et al. (2009) generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized nonapoptotic activities. Mice lacking sFasL appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL could not kill cells through Fas activation. Mice deficient in mFasL developed lymphadenopathy and hypergammaglobulinemia, similar to FasL (gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, mFasL-deficient mice (on a C57BL/6 background) succumbed to SLE (152700)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in the FasL(gld/gld) mice. O'Reilly et al. (2009) concluded that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity, and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through nonapoptotic activities.
In a patient with SLE (152700) who exhibited lymphadenopathy, Wu et al. (1996) identified a heterozygous 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion.
Lenardo (1999) suggested that this patient should be classified as having autoimmune lymphoproliferative syndrome (601859) due to mutation in the FASL gene. This form of ALPS has been designated ALPS1B, the form due to mutation in the FAS gene being ALPS1A.
Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer (211980) patients and 1,270 controls for 2 functional polymorphisms in the promoter regions of the FAS and FASL genes, -1377G-A (134637.0021) and -844T-C, respectively. Compared to noncarriers, there was a 1.6-fold increased risk of developing lung cancer for carriers of the FAS -1377AA genotype and a 1.8-fold increased risk for carriers of the FASL -844CC genotype. Carriers of both homozygous genotypes had a more than 4-fold increased risk, indicative of multiplicative gene-gene interaction.
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