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Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
Lin WY, Camp NJ, Ghoussaini M, Beesley J, Michailidou K, Hopper JL, Apicella C, Southey MC, Stone J, Schmidt MK, Broeks A, Van't Veer LJ, Th Rutgers EJ, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Peto J, Dos-Santos-Silva I, Fletcher O, Johnson N, Bolla MK, Wang Q, Dennis J, Sawyer EJ, Cheng T, Tomlinson I, Kerin MJ, Miller N, Marmé F, Surowy HM, Burwinkel B, Guénel P, Truong T, Menegaux F, Mulot C, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Benitez J, Zamora MP, Arias Perez JI, Menéndez P, González-Neira A, Pita G, Alonso MR, Alvarez N, Herrero D, Anton-Culver H, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Müller-Myhsok B, Brauch H, Brüning T, Ko YD, GENICA Network, Tessier DC, Vincent D, Bacot F, Nevanlinna H, Aittomäki K, Blomqvist C, Khan S, Matsuo K, Ito H, Iwata H, Horio A, Bogdanova NV, Antonenkova NN, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Neven P, Wauters E, Wildiers H, Lambrechts D, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Radice P, Peterlongo P, Manoukian S, Bonanni B, Couch FJ, Wang X, Vachon C, Purrington K, Giles GG, Milne RL, Mclean C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, Hassan N, Vithana EN, Kristensen V, Zheng W, Deming-Halverson S, Shrubsole MJ, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Devilee P, Tollenaar RA, Seynaeve C, Van Asperen CJ, García-Closas M, Figueroa J, Lissowska J, Brinton L, Czene K, Darabi H, Eriksson M, Brand JS, Hooning MJ, Hollestelle A, Van Den Ouweland AM, Jager A, Li J, Liu J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cross SS, Reed MW, Blot W, Signorello LB, Cai Q, Pharoah PD, Perkins B, Shah M, Blows FM, Kang D, Yoo KY, Noh DY, Hartman M, Miao H, Chia KS, Putti TC, Hamann U, Luccarini C, Baynes C, Ahmed S, Maranian M, Healey CS, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Sangrajrang S, Gaborieau V, Brennan P, Mckay J, Slager S, Toland AE, Yannoukakos D, Shen CY, Hsiung CN, Wu PE, Ding SL, Ashworth A, Jones M, Orr N, Swerdlow AJ, Tsimiklis H, Makalic E, Schmidt DF, Bui QM, Chanock SJ, Hunter DJ, Hein R, Dahmen N, Beckmann L, Aaltonen K, Muranen TA, Heikkinen T, Irwanto A, Rahman N, Turnbull CA, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Waisfisz Q, Meijers-Heijboer HE, Adank MA, Van Der Luijt RB, Hall P, Chenevix-Trench G, Dunning A, Easton DF, Cox A
(2015) Hum Mol Genet 24: 285-98
MeSH Terms: Breast Neoplasms, CASP8 and FADD-Like Apoptosis Regulating Protein, Case-Control Studies, Caspase 8, Chromosomes, Human, Pair 2, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Polymorphism, Single Nucleotide, Proteins
Show Abstract · Added January 20, 2015
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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13 MeSH Terms
Co-treatment with ginsenoside Rh2 and betulinic acid synergistically induces apoptosis in human cancer cells in association with enhanced capsase-8 activation, bax translocation, and cytochrome c release.
Li Q, Li Y, Wang X, Fang X, He K, Guo X, Zhan Z, Sun C, Jin YH
(2011) Mol Carcinog 50: 760-9
MeSH Terms: Antineoplastic Agents, Phytogenic, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Blotting, Western, Caspase 3, Caspase 8, Caspase 9, Cell Line, Tumor, Cell Survival, Cytochromes c, Dose-Response Relationship, Drug, Drug Synergism, Enzyme Activation, Flow Cytometry, Ginsenosides, HeLa Cells, Hep G2 Cells, Humans, Molecular Structure, Neoplasms, Poly(ADP-ribose) Polymerases, Protein Transport, RNA Interference, Triterpenes, bcl-2-Associated X Protein
Show Abstract · Added July 28, 2015
We provide evidence for the first time, that two natural compounds ginsenoside Rh2 (G-Rh2) and betulinic acid (Bet A) synergistically induce apoptosis in human cervical adenocarcinoma (HeLa), human lung cancer A549, and human hepatoma HepG2 cells. G-Rh2 and Bet A cooperated to induce Bax traslocation to mitochondria and cytochrome c release. Co-treatment of G-Rh2 and Bet A resulted in enhanced cleavage of caspase-8 and Bid. Moreover, specific inhibition of caspase-8 by siRNA technology effectively reduced caspase-9 processing, poly (ADP-ribose) polymerase (PARP) cleavage, caspase-3 activation, and apoptosis in co-treated cells, which indicated that the caspase-8 feedback amplification pathway may have been involved in the apoptosis process. A previous study has shown that G-Rh2 induces cancer cell apoptosis via a Bcl-2 and/or Bcl-xL-independent mechanism, and Bet A induces apoptosis mainly through a mitochondrial pathway with tumor specificity. Since the antiapoptotic Bcl-2 and Bcl-xL are frequently overexpressed in human cancer cells, combined treatment with G-Rh2 and Bet A may be a novel strategy to enhance efficacy of anticancer therapy. © 2011 Wiley-Liss, Inc.
Copyright © 2011 Wiley-Liss, Inc.
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25 MeSH Terms
Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence.
Zhang B, Beeghly-Fadiel A, Long J, Zheng W
(2011) Lancet Oncol 12: 477-88
MeSH Terms: Antigens, CD, Aromatase, Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms, CTLA-4 Antigen, Caspase 8, Cell Cycle Proteins, Checkpoint Kinase 2, DNA-Binding Proteins, Evidence-Based Medicine, Female, Genetic Predisposition to Disease, Humans, Mutation, Nuclear Proteins, Protein-Serine-Threonine Kinases, Risk Assessment, Risk Factors, Telomerase, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Show Abstract · Added December 10, 2013
BACKGROUND - More than 1000 reports have been published in the past two decades on associations between variants in candidate genes and risk of breast cancer. Results have been generally inconsistent. We did a literature search and meta-analyses to provide a synopsis of the current understanding of the genetic architecture of breast-cancer risk.
METHODS - A systematic literature search for candidate-gene association studies of breast-cancer risk was done in two stages, using PubMed on or before Feb 28, 2010. A total of 24,500 publications were identified, of which 1059 were deemed eligible for inclusion. Meta-analyses were done for 279 genetic variants in 128 candidate genes or chromosomal loci that had at least three data sources. Variants with significant associations by meta-analysis were assessed using the Venice criteria and scored as having strong, moderate, or weak cumulative evidence for an association with breast-cancer risk.
FINDINGS - 51 variants in 40 genes showed significant associations with breast-cancer risk. Cumulative epidemiological evidence of an association was graded as strong for ten variants in six genes (ATM, CASP8, CHEK2, CTLA4, NBN, and TP53), moderate for four variants in four genes (ATM, CYP19A1, TERT, and XRCC3), and weak for 37 variants. Additionally, in meta-analyses that included a minimum of 10,000 cases and 10,000 controls, convincing evidence of no association with breast-cancer risk was identified for 45 variants in 37 genes.
INTERPRETATION - Whereas most genetic variants assessed in previous candidate-gene studies showed no association with breast-cancer risk in meta-analyses, 14 variants in nine genes had moderate to strong evidence for an association. Further evaluation of these variants is warranted.
FUNDING - US National Cancer Institute.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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21 MeSH Terms
Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress.
Liu Y, Bertram CC, Shi Q, Zinkel SS
(2011) Cell Death Differ 18: 841-52
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Sequence, Animals, Ataxia Telangiectasia Mutated Proteins, BH3 Interacting Domain Death Agonist Protein, Bone Marrow Cells, Caspase 8, Cell Cycle Proteins, Cell Line, Cell Proliferation, Checkpoint Kinase 1, Chromatin, Consensus Sequence, DNA Damage, DNA Replication, DNA-Binding Proteins, Gene Deletion, Humans, Hydroxyurea, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Mutation, Missense, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, Protein Kinases, Protein-Serine-Threonine Kinases, RNA Interference, Replication Protein A, Signal Transduction, Stress, Physiological, cdc25 Phosphatases
Show Abstract · Added September 7, 2011
Proapoptotic BH3 interacting domain death agonist (Bid), a BH3-only Bcl-2 family member, is situated at the interface between the DNA damage response and apoptosis, with roles in death receptor-induced apoptosis as well as cell cycle checkpoints following DNA damage.(1, 2, 3) In this study, we demonstrate that Bid functions at the level of the sensor complex in the Atm and Rad3-related (Atr)-directed DNA damage response. Bid is found with replication protein A (RPA) in nuclear foci and associates with the Atr/Atr-interacting protein (Atrip)/RPA complex following replicative stress. Furthermore, Bid-deficient cells show an impaired response to replicative stress manifest by reduced accumulation of Atr and Atrip on chromatin and at DNA damage foci, reduced recovery of DNA synthesis following replicative stress, and decreased checkpoint kinase 1 activation and RPA phosphorylation. These results establish a direct role for the BH3-only Bcl-2 family member, Bid, acting at the level of the damage sensor complex to amplify the Atr-directed cellular response to replicative DNA damage.
1 Communities
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35 MeSH Terms
Polymorphisms and haplotypes in the caspase-3, caspase-7, and caspase-8 genes and risk for endometrial cancer: a population-based, case-control study in a Chinese population.
Xu HL, Xu WH, Cai Q, Feng M, Long J, Zheng W, Xiang YB, Shu XO
(2009) Cancer Epidemiol Biomarkers Prev 18: 2114-22
MeSH Terms: Asian Continental Ancestry Group, Case-Control Studies, Caspase 3, Caspase 7, Caspase 8, China, Endometrial Neoplasms, Female, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Middle Aged, Polymorphism, Single Nucleotide, Reproductive History, Risk Assessment, Risk Factors
Show Abstract · Added March 18, 2014
Caspase-3, caspase-7, and caspase-8 are important caspases in the apoptosis pathway and play an important role in the development and progression of cancer. We examined the association between genetic variants in the caspase-3, caspase-7, and caspase-8 genes and risk for endometrial cancer among Chinese women. Genotypes for 1,028 women with endometrial cancer and 1,003 healthy controls were determined with the Affymetrix MegAllele Targeted Genotyping System and Molecular Inversion Probe method. Of 35 selected single-nucleotide polymorphisms, four in the caspase-7 gene were in high linkage disequilibrium (rs11593766, rs3124740, rs11196445, and rs11196418) and associated with the risk for endometrial cancer. The AA genotype of rs11196418 [odds ratio, 0.36; 95% confidence interval (95% CI), 0.14-0.94] and the G allele of rs11593766 were associated with reduced risk (odds ratio of 0.75 and 95% CI of 0.59-0.96 for carriers of one G allele; odds ratio of 0.70 and 95% CI of 0.24-2.03 for carriers of two G alleles). The AA genotype of rs11196445 (odds ratio, 1.74; 95% CI, 0.99-3.05), the CC genotype of rs3124740 (odds ratio, 1.36; 95% CI, 1.06-1.75), and the GG genotype of rs10787498 in the caspase-7 gene (odds ratio, 1.90; 95% CI, 1.16-3.11) were associated with increased risk compared with homozygotes of the major alleles. The gene-disease association seemed to be more pronounced among premenopausal women, although tests for multiplicative interaction between genes and menopausal status failed to reach statistical significance. The GG genotype of rs2705901 in the caspase-3 gene was significantly associated with increased cancer risk compared with the CC genotype (odds ratio, 2.25; 95% CI, 1.03-4.95). No association was observed between polymorphisms of the caspase-8 gene and risk for endometrial cancer. These findings suggest that genetic variants in caspase-3 and caspase-7 may play a role in endometrial cancer susceptibility.
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17 MeSH Terms
IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression.
Yang D, Wang S, Brooks C, Dong Z, Schoenlein PV, Kumar V, Ouyang X, Xiong H, Lahat G, Hayes-Jordan A, Lazar A, Pollock R, Lev D, Liu K
(2009) Cancer Res 69: 1080-8
MeSH Terms: Animals, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspase 8, Caspase Inhibitors, Cell Line, Tumor, Enzyme Activation, Fas Ligand Protein, Humans, Immunohistochemistry, Interferon Regulatory Factors, Mice, Mitochondria, RNA, Messenger, RNA, Small Interfering, Receptors, TNF-Related Apoptosis-Inducing Ligand, Sarcoma, Sarcoma, Experimental, TNF-Related Apoptosis-Inducing Ligand
Show Abstract · Added September 12, 2016
IFN regulatory factor 8 (IRF8) has been shown to suppress tumor development at least partly through regulating apoptosis of tumor cells; however, the molecular mechanisms underlying IRF8 regulation of apoptosis are still not fully understood. Here, we showed that disrupting IRF8 function resulted in inhibition of cytochrome c release, caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase cleavage in soft tissue sarcoma (STS) cells. Inhibition of the mitochondrion-dependent apoptosis signaling cascade is apparently due to blockage of caspase-8 and Bid activation. Analysis of signaling events upstream of caspase-8 revealed that disrupting IRF8 function dramatically increases FLIP mRNA stability, resulting in increased IRF8 protein level. Furthermore, primary myeloid cells isolated from IRF8-null mice also exhibited increased FLIP protein level, suggesting that IRF8 might be a general repressor of FLIP. Nuclear IRF8 protein was absent in 92% (55 of 60) of human STS specimens, and 99% (59 of 60) of human STS specimens exhibited FLIP expression, suggesting that the nuclear IRF8 protein level is inversely correlated with FLIP level in vivo. Silencing FLIP expression significantly increased human sarcoma cells to both FasL-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and ectopic expression of IRF8 also significantly increased the sensitivity of these human sarcoma cells to FasL- and TRAIL-induced apoptosis. Taken together, our data suggest that IRF8 mediates FLIP expression level to regulate apoptosis and targeting IRF8 expression is a potentially effective therapeutic strategy to sensitize apoptosis-resistant human STS to apoptosis, thereby possibly overcoming chemoresistance of STS, currently a major obstacle in human STS therapy.
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19 MeSH Terms
Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes.
Biju MP, Neumann AK, Bensinger SJ, Johnson RS, Turka LA, Haase VH
(2004) Mol Cell Biol 24: 9038-47
MeSH Terms: Animals, Apoptosis, Caspase 8, Caspases, Cell Survival, DNA-Binding Proteins, Gene Deletion, Gene Expression Regulation, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, In Situ Nick-End Labeling, Mice, Mice, Inbred Strains, Mice, Knockout, Mice, Transgenic, Nuclear Proteins, Thymus Gland, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease
Show Abstract · Added August 19, 2013
The von Hippel-Lindau gene product (pVHL) targets the alpha subunit of basic helix-loop-helix transcription factor hypoxia-inducible factor (HIF) for proteasomal degradation. Inactivation of pVhl in the mouse germ line results in embryonic lethality, indicating that tight control of Hif-mediated adaptive responses to hypoxia is required for normal development and tissue function. In order to investigate the role of pVhl in T-cell development, we generated mice with thymocyte-specific inactivation of Vhlh resulting in constitutive transcriptional activity of Hif-1, as well as mice with thymocyte-specific repression of Hif-1 in a wild-type and Vhlh-deficient background. Thymi from Vhlh-deficient mice were small due to a severe reduction in the total number of CD4/CD8-double-positive thymocytes which was associated with increased apoptosis in vivo and in vitro. Increased apoptosis was a result of enhanced caspase 8 activity, while Bcl-2 and Bcl-XL transgene expression had little effect on this phenotype. Inactivation of Hif-1 in Vhlh-deficient thymocytes restored thymic cellularity as well as thymocyte viability in vitro. Our data suggest that tight regulation of Hif-1 via pVhl is required for normal thymocyte development and viability and that an increase in Hif-1 transcriptional activity enhances caspase 8-mediated apoptosis in thymocytes.
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24 MeSH Terms
The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis.
Filippova M, Song H, Connolly JL, Dermody TS, Duerksen-Hughes PJ
(2002) J Biol Chem 277: 21730-9
MeSH Terms: 3T3 Cells, Animals, Antigens, CD, Apoptosis, Caspase 3, Caspase 8, Caspase 9, Caspases, Cell Death, Cell Survival, Ceramides, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Genes, Reporter, Genes, p53, Humans, Immunoblotting, Mice, Mitomycin, Oncogene Proteins, Viral, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Proteins, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Repressor Proteins, Signal Transduction, TNF Receptor-Associated Factor 1, Time Factors, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Tumor Suppressor Protein p53, Two-Hybrid System Techniques, U937 Cells
Show Abstract · Added December 10, 2013
High risk strains of human papillomavirus (HPV), such as HPV 16, cause human cervical carcinoma. The E6 protein of HPV 16 mediates the rapid degradation of p53, although this is not the only function of E6 and cannot completely explain its transforming potential. Previous work in our laboratory has demonstrated that transfection of HPV 16 E6 into the tumor necrosis factor (TNF)-sensitive LM cell line protects expressing cells from TNF-induced apoptosis in a p53-independent manner, and the purpose of this study was to determine the molecular mechanism underlying this protection. Caspase 3 and caspase 8 activation were significantly reduced in E6-expressing cells, indicating that E6 acts early in the TNF apoptotic pathway. In fact, E6 binds directly to TNF R1, as shown both by co-immunoprecipitation and mammalian two-hybrid approaches. E6 requires the same C-terminal portion of TNF R1 for binding as does TNF R1-associated death domain, and TNF R1/TNF R1-associated death domain interactions are decreased in the presence of E6. HA-E6 also blocked cell death triggered by transfection of the death domain of TNF R1. Together, these results provide strong support for a model in which HPV E6 binding to TNF R1 interferes with formation of the death-inducing signaling complex and thus with transduction of proapoptotic signals. They also demonstrate that HPV, like several other viruses, has developed a method for evading the TNF-mediated host immune response.
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37 MeSH Terms
Death and survival signals determine active/inactive conformations of pro-apoptotic BAX, BAD, and BID molecules.
Korsmeyer SJ, Gross A, Harada H, Zha J, Wang K, Yin XM, Wei M, Zinkel S
(1999) Cold Spring Harb Symp Quant Biol 64: 343-50
MeSH Terms: Animals, Antigens, CD, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Biological Transport, Active, Carrier Proteins, Caspase 8, Caspase 9, Caspases, Cell Death, Cell Survival, Dimerization, Humans, Mitochondria, Models, Biological, Models, Molecular, Phosphorylation, Protein Conformation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, bcl-2-Associated X Protein, bcl-Associated Death Protein, fas Receptor
Added September 7, 2011
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26 MeSH Terms
NMR structure and mutagenesis of the FADD (Mort1) death-effector domain.
Eberstadt M, Huang B, Chen Z, Meadows RP, Ng SC, Zheng L, Lenardo MJ, Fesik SW
(1998) Nature 392: 941-5
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Apoptosis, Carrier Proteins, Caspase 8, Caspase 9, Caspases, Crystallography, X-Ray, Cysteine Endopeptidases, Fas-Associated Death Domain Protein, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Protein Folding, Protein Structure, Secondary, fas Receptor
Show Abstract · Added March 5, 2014
When activated, membrane-bound receptors for Fas and tumour-necrosis factor initiate programmed cell death by recruiting the death domain of the adaptor protein FADD to the membrane. FADD then activates caspase 8 (also known as FLICE or MACH) through an interaction between the death-effector domains of FADD and caspase 8. This ultimately leads to the apoptotic response. Death-effector domains and homologous protein modules known as caspase-recruitment domains have been found in several proteins and are important regulators of caspase (FLICE) activity and of apoptosis. Here we describe the solution structure of a soluble, biologically active mutant of the FADD death-effector domain. The structure consists of six antiparallel, amphipathic alpha-helices and resembles the overall fold of the death domains of Fas and p75. Despite this structural similarity, mutations that inhibit protein-protein interactions involving the Fas death domain have no effect when introduced into the FADD death-effector domain. Instead, a hydrophobic region of the FADD death-effector domain that is not present in the death domains is vital for binding to FLICE and for apoptotic activity.
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18 MeSH Terms