The role of Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis in vivo and in vitro
Hongna SunYanmei YangMuyu GuYang LiZhe JiaoChunqing LuBingyu LiYuting JiangLixin JiangFang ChuWenjing YangDianjun SunYanhui Gao
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Abstract:
The molecular mechanisms underlying arsenic-induced neurotoxicity have not been completely elucidated. Our study aimed to determine the role of the Fas-FasL-FADD signaling pathway in arsenic-mediated neuronal apoptosis. Pathological and molecular biological tests were performed on the cerebral cortex of arsenic-exposed rats and SH-SY5Y neuroblastoma cells. Arsenic induced apoptosis in the cortical neurons, which corresponded to abnormal ultrastructural changes. Mechanistically, arsenic activated the Fas-FasL-FADD signaling pathway and the downstream caspases both in vivo and in vitro. ZB4 treatment reversed the apoptotic effects of arsenic on the SHSY5Y cells. Taken together, arsenic induces neurotoxicity by activating the Fas-FasL-FADD signaling pathway.Keywords:
FADD
Fas ligand
Neurotoxicity
Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL
Fas activation triggers apoptosis in many cell types. Studies with anti-Fas antibodies have produced conflicting results on Fas signaling, particularly the role of the Bcl-2 family in this process. Comparison between physiological ligand and anti-Fas antibodies revealed that only extensive Fas aggregation, by membrane bound FasL or aggregated soluble FasL consistently triggered apoptosis, whereas antibodies could act as death agonists or antagonists. Studies on Fas signaling in cell lines and primary cells from transgenic mice revealed that FADD/MORT1 and caspase-8 were required for apoptosis. In contrast, Bcl-2 or Bcl-x L did not block FasL-induced apoptosis in lymphocytes or hepatocytes, demonstrating that signaling for cell death induced by Fas and the pathways to apoptosis regulated by the Bcl-2 family are distinct.
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Caspase 8
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Caspase 10
NLRP1
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Caspase 2
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A number of "suicide genes" have been developed as safety switches for gene therapy vectors or as potential inducible cytotoxic agents for hyperproliferative disorders, such as cancer or restenosis. However, most of these approaches have relied on foreign proteins, such as HSV thymidine kinase, that primarily target rapidly dividing cells. In contrast, novel artificial death switches based on chemical inducers of dimerization (CIDs) and endogenous proapoptotic molecules function efficiently in both dividing and nondividing cells. In this approach, lipid-permeable, nontoxic CIDs are used to conditionally cross-link target proteins that are fused to CID-binding domains (CBDs), thus activating signaling cascades leading to apoptosis. In previous reports, CID-regulated Fas and caspases 1, 3, 8, and 9 were described. Since the maximum efficacy of these artificial death switches requires low basal and high specific activity, we have optimized these death switches for three parameters: (1) extent of oligomerization, (2) spacing between CBDs and target proteins, and (3) intracellular localization. We describe improved conditional Fas and caspase 1, 3, 8, and 9 alleles that function at subnanomolar levels of the CID AP1903 to trigger apoptosis. Further, we demonstrate for the first time that oligomerization of the death effector domain of the Fas-associated protein, FADD, is sufficient to trigger apoptosis, suggesting that the primary function of FADD, like that of Apaf-1, is oligomerization of associated caspases. Finally, we demonstrate that nuclear-targeted caspases 1, 3, and 8 can trigger apoptosis efficiently, implying that the cleavage of nuclear targets is sufficient for apoptosis.
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The Fas/CD95 receptor-ligand system plays an essential role in apoptosis that contributes to secondary damage after spinal cord injury (SCI), but the mechanism regulating the efficiency of FasL/Fas signaling in the central nervous system (CNS) is unknown. Here, FasL/Fas signaling complexes in membrane rafts were investigated in the spinal cord of adult female Fischer rats subjected to moderate cervical SCI and sham operation controls. In sham-operated animals, a portion of FasL, but not Fas was present in membrane rafts. SCI resulted in FasL and Fas translocation into membrane raft 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). Moreover, SCI induced expression of Fas in clusters around the nucleus in both neurons and astrocytes. The formation of the DISC signaling platform leads to rapid activation of initiator caspase-8 and effector caspase-3, and the modification of signaling intermediates such as FADD and cFLIPL . Thus, FasL/Fas-mediated signaling after SCI is similar to Fas expressing Type I cell apoptosis.
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E1B 19K, the adenovirus Bcl-2 homologue, is a potent inhibitor of apoptosis induced by various stimuli including Fas and tumor necrosis factor-α. Fas and TNFR-1 belong to a family of cytokine-activated receptors that share key components in their signaling pathways, Fas-associating protein with death domain (FADD) and FADD-like interleukin-1β–converting enzyme (FLICE), to induce an apoptotic response. We demonstrate here that E1B 19K and Bcl-xL are able to inhibit apoptosis induced by FADD, but not FLICE. Surprisingly, apoptosis was abrogated by E1B 19K and Bcl-xL when FADD and FLICE were coexpressed. Immunofluorescence studies demonstrated that FADD expression produced large insoluble death effector filaments that may represent oligomerized FADD. E1B 19K expression disrupted FADD filament formation causing FADD and FLICE to relocalize to membrane and cytoskeletal structures where E1B 19K is normally localized. E1B 19K, however, does not detectably bind to FADD, nor does it inhibit FADD and FLICE from being recruited to the death-inducing signaling complex (DISC) when Fas is stimulated. Thus, E1B 19K may inhibit Fas-mediated cell death downstream of FADD recruitment of FLICE but upstream of FLICE activation by disrupting FADD oligomerization and sequestering an essential component of the DISC.
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Objective To investigate the effects of the gene expressions of FAS、FASL、FADD and caspase-8 in esophageal carsinogenesis. Methods Immunohistochemical method was applied to detect the expression of FAS、FASL、FADD and caspase-8 proteins in esophageal epithelium. In situ hybridization method was applied to detect the expression of FADD and caspase-8 mRNA in esophageal epithelium. Results The positive rates of FAS, FADD and caspase-8 proteins and FADD、caspase-8 mRNA were decreased from normal epithelium to dysplasia and carcinoma tissues gradually. The positive rates of FASL protein were increased from normal epithelium to dysplasia and carcinoma tissues gradually. There was very significant statistical difference between carcinoma and normal epithelium(P0.05). The expression of FAS、FASL and caspase-8 was correlated with the degree of tumor differentiation(P0.05). ConclusionThe abnormal expression of FAS and FASL maybe relate with the pathogenesis of esophageal carcinoma and is also involved in the degree of differentiation and the immune escape. FADD and caspase-8 expression maybe plays an important role in esophageal carsinogenesis.
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RIPK1
TRADD
Caspase 8
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Fas ligand
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Objective To investigate the effects of the gene expressions of FAS、FASL、 FADD and caspase-8 in esophageal carsinogenesis. Methods Immunohistochemical method was applied to detect the expression of FAS、FASL、FADD and caspase-8 proteins in esophageal epithelium. In situ hybridization method was applied to detect the expression of FADD and caspase-8 mRNA in esophageal epithelium. Results The positive rates of FAS, FADD and caspase-8 proteins and FADD、caspase-8 mRNA were decreased from normal epithelium to dysplasia and carcinoma tissues gradually. The positive rates of FASL protein were increased from normal epithelium to dysplasia and carcinoma tissues gradually. There was very significant statistical difference between carcinoma and normal epithelium (P＜0.05). The expression of FAS、FASL and caspase-8 was correlated with the degree of tumor differentiation (P＜0.05). Conclusion The abnormal expression of FAS and FASL maybe relate with the pathogenesis of esophageal carcinoma and is also involved in the degree of differentiation and the immune escape. FADD and caspase-8 expression maybe plays an important role in esophageal carsinogenesis.
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To investigate the expression of five apoptosis-related proteins, Fas, Fas ligand (FasL), Fas-associated death domain protein (FADD), caspase 8, and mutant p53, in human esophageal squamous cell carcinoma (ESCC) tissue, and analyze the association of these proteins with ESCC malignant progression.116 ESCC specimens obtained during operation. Tissue microarray composed of the 116 specimens of cancerous tissues and corresponding paracancerous normal epithelium tissues was constructed. The expression of Fas, FasL, FADD, caspase 8, and mutant p53 was detected in the ESCC tissues and paracancerous normal epithelium tissues and analysis was conducted for the correlation between the expression of these proteins and the pathoclinical features and prognosis. involvement, differentiated grade, pTNM stages and disease-free survival.The positive rate of Fas in the ESCC tissues was 41.4%, significantly lower than that in the normal squamous epithelium was 95.7%, P < 0.001). The positive rates of FasL and FADD in the ESCC tissues were 76.7% and 50.0%, both significantly higher than those in the normal squamous epithelium (39.7% and 7.8%, both P < 0.001). Caspase 8 was strongly positive in the whole normal esophageal epithelium tissue except basal and superbasal cells, but negative in ESCC. Mutant p53 protein was negative in the normal esophageal epithelium tissue, with only several cases positive in the basal cells, but was diffusely positive in ESCC tissues with a positive rate of 37.1%. The expression of Fas in the well and moderately differentiated ESCC tissues was significantly higher than in the poorly differentiated ones (P = 0.022). The patients with positive expression of FADD had lower disease-free survival rate (P = 0.0028). The expression of Fas, FasL, caspase 8, and mutant p53 was not related with disease-free survival rate (P > 0.05).The apoptosis-related markers, such as Fas, FasL, FADD, caspase 8, and mutant p53 protein may play important roles in the development and progression of ESCC, and FADD can be used as a marker to predict the advance and prognosis of ESCC.
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