Disease relevance of FAS

• CONCLUSIONS: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer [1].
• ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression [1].
• Death ligands have been explored as potential therapeutics in cancer therapy with some limitations in the case of FAS and TNF due to toxicities [2].
• Several groups have searched for mutations in the FAS receptor, a well-characterized apoptotic protein carrying a death domain, and reported the existence of rare mutations in multiple myeloma, T-acute lymphoblastic leukemia (T-ALL), and adult T-cell leukemia [3].
• Mutation analysis of the FAS and TNFR apoptotic cascade genes in hematological malignancies [3].

Psychiatry related information on FAS

• Apoptosis, triggered by the activation of CD95 (Fas), is one of the most important defense mechanisms against UV light-induced carcinogenesis in experimental models, but the dynamics of CD95 expression in patients with sun-induced lesions are largely unknown [4].
• The previously associated marker, located in the promoter of TNFRSF6, now gave significant association with cognitive status in the Scottish early-onset dementia samples (p = 0.005) with the strongest signals being evident in the APOE-e4 carrier subgroup, thus providing a second independent positive result for this marker [5].
• Upregulation of p53 and APO-1/Fas (CD95) precedes apoptosis in many cell types, and a potential role for these molecules has already been demonstrated in Alzheimer's disease (AD) and several other neurodegenerative diseases [6].
• The severity of the dysmorphic features was related to degree of mental deficiency; children with the most severe manifestations of FAS had an average IQ of 55, whereas children with lesser manifestations had an average IQ of 82 [7].
• Fourteen patients with Parkinson's disease underwent a full battery of neuropsychological testing including performance and verbal subtests of the WAIS-R, Boston naming test, FAS test, and California verbal learning test [8].

High impact information on FAS

• The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95 [9].
• FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex [10].
• The subsequent interaction of FasL with Fas (CD95) displayed on neighbouring cells, including HIV-1-specific cytotoxic T lymphocytes, may lead to bystander cell killing and thus forms an important mechanism of immune evasion [11].
• This article focuses on death receptor-associated apoptosis and the role of CD95 (Apo-1/Fas)-mediated signalling in T-cell and B-cell development and during the course of an immune response [12].
• Tumor cells may also evade immune attack by expressing CD95 (APO-1/Fas) ligand or other molecules that induce apoptosis in activated T cells [13].

Chemical compound and disease context of FAS

• FAS/FAS ligand ratio: a marker of oxaliplatin-based intrinsic and acquired resistance in advanced colorectal cancer [1].
• Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells [14].
• Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance [15].
• We have shown previously that resveratrol-induced apoptosis of a human colon cancer cell line involved the redistribution of CD95 (Fas/Apo-1) into lipid rafts [16].
• In this study, we investigated the impact of the HDACi valproic acid (VA) on TRAIL- and CD95-mediated apoptosis in hepatoma cells, as well as its sensitizing effect on a chemotherapeutic agent [17].

Biological context of FAS

• The FAS-associated via death domain (FADD) gene that acts downstream of the FAS cascade as a key gene to induce apoptosis was more than 10-fold down-regulated in MCL [18].
• We report that FADD (FAS-associated death domain protein) and caspase-8 were constitutively expressed in lymphoma B cells and that the CD95 pathway was blocked upstream to caspase-8 activation [19].
• CONCLUSIONS: The FAS -1377A/-670A haplotype in combination with FASL -844C is associated with cervical carcinogenesis [20].
• The present study examines the hypothesis that genetic polymorphisms in FAS and FAS ligand genes, alone or in combination, are associated with cervical carcinogenesis [20].
• Furthermore, the expression of FAS which is known to be pro-apoptotic is markedly decreased favoring the CD40 mediated cell survival pathway in these cells [21].

Anatomical context of FAS

• Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand [22].
• Arsenic induces human keratinocyte apoptosis by the FAS/FAS ligand pathway, which correlates with alterations in nuclear factor-kappa B and activator protein-1 activity [23].
• Based on semiquantitative RT-PCR analysis, CCL2 did not alter either FAS or FASLG mRNA expression in endometrial stromal cells [24].
• Eight myeloma cell lines with variable expression of bcl-2 were screened for the expression of the FAS antigen and for sensitivity to anti-FAS-induced apoptosis [25].
• When assayed for bioactivity, vesicles from unexposed cells induced the greatest level of apoptosis in TNFRSF6 (formerly known as FAS) receptor-bearing Jurkat cells (cell surviving fraction of 43.7 +/- 6.1; P < 0.05), followed by vesicles collected from cells treated with 4 Gy (79.6 +/- 2.6%; P < 0.05) [26].

Associations of FAS with chemical compounds

• A fraction of this protein is highly phosphorylated at serine/threonine residues, with both phosphorylated and unphosphorylated forms being capable of binding to FAS [27].
• However, disruption of either FAS or TNFR1 signaling did not interfere with the Zeocin induced apoptotic response in our experimental system [28].
• The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-1/CD95- and ceramide-induced apoptosis [29].
• We report here that anticancer drugs such as doxorubicin lead to induction of the CD95 (APO-1/Fas) system of apoptosis and the cellular stress pathway which includes JNK/SAPKs [30].
• Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases [31].

Physical interactions of FAS

• TAp63alpha directly transactivates the CD95 gene via the p53 binding site in the first intron resulting in upregulation of a functional CD95 death receptor [32].
• We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein [33].
• Induction of FAS-mediated signaling was followed by a rapid decrease in HSF1-DNA binding and inducible hsp70 expression [34].
• In these cells, the mutated ezrin did not co-localize or co-immunoprecipitate with CD95 [35].
• BACKGROUND AND OBJECTIVES: Fas (APO-1) induces apoptosis after binding Fas ligand (FasL) [36].

Enzymatic interactions of FAS

• FAP-1 dephosphorylates phospho-tyrosine 275 in the carboxyl terminus of FAS [37].
• We show that K8 is strongly phosphorylated on Ser-73 upon stimulation of the pro-apoptotic cytokine receptor Fas/CD95/Apo-1 in HT-29 cells [38].
• CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4(+)T lymphocytes [39].

Co-localisations of FAS

• Here we show that human T cells that are susceptible to CD95-mediated apoptosis, exhibit a constitutive polarized morphology, and that CD95 colocalizes with ezrin at the site of cellular polarization [40].

Regulatory relationships of FAS

• CD4 T cell lines can induce apoptosis of CD40-activated CLL cells via a CD95 ligand (CD95-L)-dependent mechanism [41].
• A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine [14].
• We conclude that JNK inhibition has antitumor activity by inducing growth arrest and enhancing CD95-mediated apoptosis by a transcription-independent mechanism [42].
• Taken together these results suggest that apoptosis signaling by TNF is distinct from that induced by CD95 and TRAIL [43].
• Taken together, our results functionally establish FADD as the apoptotic trigger of CD95 and TNFR-1 [44].
• We therefore propose that induction of the short c-FLIP isoforms inhibits the onset of CD95-induced apoptosis in primary CD40-stimulated ALL cells despite high CD95 expression [45].

Other interactions of FAS

• Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95 [46].
• Apoptosis induced by DNA damage and other stresses can proceed via expression of Fas ligand (FasL) and ligation of its receptor, Fas (CD95) [47].
• Despite expression of other NF-kappaB-dependent antiapoptotic proteins, the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize HRS cells to CD95 and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis [48].
• Down-regulation of FLIP with an antisense oligonucleotide or a pharmacologic agent, however, was not sufficient to render CLL cells sensitive to CD95-mediated apoptosis in the 24-72 h after CD40 activation [41].
• Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking [33].

Analytical, diagnostic and therapeutic context of FAS

• Real-time PCR analysis revealed that FAS and FASLG were largely increased following N-9 treatment [49].
• The expression of adhesion and co-stimulatory molecules, and chemokine and death receptors such as tumour necrosis factor (TNF) and FAS on acute myeloid leukaemia (AML) may influence the biology of the disease and response to chemotherapy and immunotherapy [50].
• Triggering of the CD95 pathway in HRS cells is indicated by the presence of CD95L in cells surrounding them as well as confocal microscopy showing c-FLIP predominantly localized at the cell membrane [48].
• Patients with chronic lymphocytic leukemia (CLL) treated with adenovirus (Ad)-CD154 (CD40L) gene therapy experience reductions in leukemia cell counts and lymph node size associated with induction of the death receptor Fas (CD95) [41].
• Previously, CD95 DISC composition was analyzed by two-dimensional gel electrophoresis and four major cytotoxicity-associated proteins (CAP1-4) were found [51].
• Our study demonstrates that therapeutic preparations of normal human IgG for i.v. use (i.v.Ig) induces apoptosis in leukemic cells of lymphocyte and monocyte lineage and in CD40-activated normal tonsillar B cells, involving, at least in part, Fas (CD95/APO-1) and activation of caspases. We identified and purified functional Fas reactive molecules in the I.v.Ig preparation. These results provide evidence for a role of Fas in the mechanisms of action of i.v.Ig in autoimmune diseases, and suggest a role of normal Ig in controlling cell death and proliferation [52].

References