Death Domain Gene Research Articles

Corrigendum: A new variant of the ectodysplasin A receptor death domain gene associated with anhidrotic ectodermal dysplasia in a Turkish family and its simple diagnosis by restriction fragment length polymorphism [Genes Genet. Syst. (2023) 98, p. 171–178

Corrigendum: A new variant of the ectodysplasin A receptor death domain gene associated with anhidrotic ectodermal dysplasia in a Turkish family and its simple diagnosis by restriction fragment length polymorphism [Genes Genet. Syst. (2023) 98, p. 171–178

A new variant of the ectodysplasin A receptor death domain gene associated with anhidrotic ectodermal dysplasia in a Turkish family and its simple diagnosis by restriction fragment length polymorphism.

Ectodermal dysplasia (ED), which exhibits a wide range of clinical symptoms, may be classified into three major types: hypohidrotic, anhidrotic, and hidrotic. A male child (proband) showing anhidrotic dysplasia was used as the subject of this study. The biopsy of the big toe revealed that the male child had no sweat glands. Genetic analysis of the patient revealed a mutation caused by a homozygous nucleotide substitution in the EDAR-associated death domain (EDARADD) (rs114632254) gene c.439G>A (p.Gly147Arg). Phenotypically, his teeth were sharp, but eight teeth were missing (oligodontia). The patient had normal nails with dry skin, sparse hair, everted lower lip vermilion, hyperpigmented eyelids, and abnormal nasal bridge morphology around the eyes. There is also a homozygous dominant (healthy) female and a heterozygous male in this family, who are cousins (aunt children) to the heterozygous parents. The daughter of the patient was also heterozygous. This mutation represents homozygous recessive inheritance, which we describe for the first time. Furthermore, we demonstrated that this genetic disorder can be readily diagnosed using the restriction fragment length polymorphism (RFLP) method after digestion with MnII restriction endonuclease.

Targeting Fas-associated protein with death domain gene with chitosan-lipid nanoparticles inhibits coronary heart disease progression in mice

Cell apoptosis or programmed cell death is a physiological phenomenon during the development of the body; however, under certain pathological conditions, insufficient, or excessive apoptosis can cause tissue damage and physiological dysfunction. This study investigated the inhibition of oxidized low-density lipoprotein (oxLDL)-induced macrophage apoptosis in mice with coronary heart disease by regulating the target Fasassociated protein with death domain (FADD) gene. We used Western blotting to measure the effect of oxLDL on mouse macrophages and observe the effects of adding simvastatin, 3-methyladenine (3-MA), self-blocking, and other drugs. The results indicated that the target FADD gene played an important role in inhibiting lactate dehydrogenase release by 13%, in the process of oxLDL-induced lipid aggregation in macrophages. The EC50 observed by dual acridine orange/ethidium bromide fluorescence-staining accounts for the proportion of FADD being reduced by 32%, indicating that the target FADD gene exhibited a significant inhibitory effect on oxLDL-induced macrophage apoptosis in coronary heart disease. This study used a novel chitosan-lipid nanoparticle as a gene carrier to significantly improve efficacy. Therefore, targeting the FADD gene using novel chitosan-lipid nanoparticles to deliver siRNA could be a potential clinical treatment in coronary heart disease.

Generation and characterization of mice bearing null alleles of nradd/Nrh2.

The Neurotrophin receptor associated death domain gene (Nradd/Nrh2/Plaidd) is a type I transmembrane protein with a unique and short N-terminal extracellular domain and a transmembrane and intracellular domain that bears high similarity to the p75 neurotrophin receptor (p75NTR/Ngfr). Initial studies suggested that NRADD regulates neurotrophin signaling but very little is known about its physiological roles. We have generated and characterized NRADD conditional and germ-line null mouse lines. These mice are viable and fertile and dońt show evident abnormalities. However, NRADD deletion results in an increase in the proportion of dorsal root ganglion neurons expressing p75NTR. The NRADD conditional and complete knockout mouse lines generated are new and useful tools to study the physiological roles of NRADD. Birth Defects Research (Part A) 106:605-612, 2016. © 2016 Wiley Periodicals, Inc.

FADD expression is associated with regional and distant metastasis in squamous cell carcinoma of the head and neck

The Fas-associated death domain gene (FADD) is often overexpressed in squamous cell carcinoma of the head and neck (HNSCC), and is considered to be a driver gene in amplification of the chromosomal 11q13.3 region. Amplification of 11q13.3 is associated with increased metastasis in HNSCC and breast cancer. The aim of this study was to investigate the association between FADD protein expression in advanced-stage HNSCC and clinicopathological features and outcome. Tumour tissues of 177 HNSCC patients uniformly treated with primary surgery and postoperative radiotherapy were collected. FADD expression was assessed on pretreatment tumour biopsies using immunohistochemistry. High FADD expression was detected in 44% of the HNSCC patients. High expression was associated with an increased rate of lymph node metastasis (P = 0.001) and with a shorter distant metastasis-free interval (DMFI) (HR 2.6, 95% CI 1.0-6.7, P = 0.046) when lymph node metastases were present. Our data show that an increase in FADD expression is associated with a higher incidence of lymph node metastasis at presentation, and with shorter DMFI when lymph node metastases are present. High FADD expression in the primary tumour could be a useful marker to select patients for systemic treatment strategies that reduce the risk of distant metastases.

Abstract 5653: The in vitro effects of aloe-emodin on head and neck squamous cell carcinoma

Abstract Aloe emodin (AE) is an anthraquinone compound extracted from the leaves of aloe vera plants, which has been shown to have anti-neoplastic activities on various cancers. This study investigated the effects of AE on cell proliferation and apoptosis induction in head and neck squamous cell carcinoma (HNSCC) using a HEP-2 cell line model. HEP-2 cells were either left untreated, normal media, (Control) or treated with different concentrations of AE (6.25-100 µM) for 24 h. Cell proliferation was evaluated using MTS and crystal violet staining assays. Cell cycle was analysed using flow cytometry measuring DNA content (Propidum Iodide). Apoptosis was analysed by TUNEL and apoptotic gene expression was measured by human apoptosis RT2 Profilertm polymerase chain reaction array. Cell proliferation assays showed that AE inhibited cell proliferation in a dose dependent manner. MTS assay demonstrated a 26.96% and 43.12% decrease in cell proliferation at 6.25 and 12.5 µM, respectively. In confirmation of the MTS assay, crystal violet staining displayed 35.58% and 39.42% reduction in cell proliferation at 6.25 and 12.5 µM, respectively. Further, AE treatment demonstrated an increase in G1 cell cycle arrest compared to the control. Apoptosis analysis exhibited an increase in early and late stage apoptotic cells in the AE treated group. TUNEL assay demonstrated a 2 to 3 fold increase in apoptosis compared to the control. Finally, the apoptotic gene expression array revealed differential expression among the 12.5 µM AE treated cells and control cells of several genes involved in apoptosis including: TNF, BCL2, caspase and death domain gene families. In conclusion, we present original data for the first time showing AE is capable of producing anti-neoplastic effects, inhibiting cell proliferation and inducing apoptosis, in HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5653.

Splenic marginal zone lymphomas are characterized by loss of interstitial regions of chromosome 7q, 7q31.32 and 7q36.2 that include the protection of telomere 1 (POT1) and sonic hedgehog (SHH) genes

To further characterize the genotypic features of splenic (S) and nodal (N) marginal zone lymphomas (MZL) we compared eight SMZL and five NMZL by array-based comparative genomic hybridization (aCGH). Arbitrarily, aberrations were divided into major imbalances, defined as gains or losses involving five or more contiguous genetic loci, and minor imbalances, defined as those involving four or fewer loci. SMZL, but not NMZL, demonstrated major imbalances. These included deletions involving various lengths of 7q (three cases), and 14q23q24 (one case) and gains of 9p13p21 (one case), 13q21q33 (one case) and 16p13.1 (one case). Common minor imbalances in SMZL were: loss of sonic hedgehog gene (SHH) at 7q36.2 (four cases), loss of protection of telomere 1 gene (POT1) at 7q31.32 (three cases), and gain of glioma associated oncogene 1 (GLI1) at 12q13.2 (three cases). Common minor alterations in NMZL were: loss of the fas-associated via death domain gene (FADD) at 11q13.2 (three cases) and gain of GLI1 (five cases). In conclusion, SMZL, but not NMZL, demonstrates large genomic imbalances and frequent loss of the 7q31.32 and 7q36.2 regions involving POT1 and SHH, respectively. In NMZL, loss of FADD and gain of GLI1 are frequent events.

Amplicon Mapping and Expression Profiling Identify the Fas-Associated Death Domain Gene as a New Driver in the 11q13.3 Amplicon in Laryngeal/Pharyngeal Cancer

Amplification of the 11q13 region is a frequent event in human cancer. The highest incidence (36%) is found in head and neck squamous cell carcinomas. Recently, we reported that the amplicon size in 30 laryngeal and pharyngeal carcinomas with 11q13 amplification is determined by unique genomic structures, resulting in the amplification of a set of genes rather than a single gene. To investigate which gene(s) drive the 11q13 amplicon, we determined the smallest region of overlap with amplification and the expression levels of all genes within this amplicon. Using array-based comparative genomic hybridization analysis, we detected a region of approximately 1.7 Mb containing 13 amplified genes in more than 25 of the 29 carcinomas. Quantitative reverse transcription-PCR revealed that overexpression of 8 potential driver genes including, cyclin D1, cortactin, and Fas-associated death domain (FADD), correlated significantly with DNA amplification. FADD protein levels correlated well with DNA amplification, implicating that FADD is also a candidate driver gene in the 11q13 amplicon. Analysis of 167 laryngeal carcinomas showed that increased expression of FADD (P = 0.007) and Ser(194) phosphorylated FADD (P = 0.011) were associated with a worse disease-specific survival. FADD was recently reported to be involved in cell cycle regulation, and cancer cells expressing high levels of the Ser(194) phosphorylated isoform of FADD proved to be more sensitive to Taxol-induced cell cycle arrest. Because of the frequent amplification of the 11q13 region and concomitant overexpression of FADD in head and neck squamous cell carcinomas, we hypothesize that FADD is a marker to select patients that might benefit from Taxol-based chemoradiotherapy.

Characterization of bovine FAS‐associated death domain gene1

The FAS-associated death domain (FADD) protein is an adapter/signaling molecule that has been shown to function in human cells to promote apoptosis and to inhibit NF-kappaB activation. Because of the critical role that apoptosis and NF-kappaB play in a variety of disease states, we mapped the bovine FADD gene, sequenced bovine FADD cDNA, and characterized its expression in endothelial cells (EC). Sequencing of bovine FADD revealed approximately 65 and 58% amino acid sequence identity to its human and murine homologues, respectively. Bovine FADD was mapped to chromosome 29 by radiation hybrid mapping. In addition, the functionality of bovine FADD was studied. Expression of a bovine FADD dominant-negative construct blocked bacterial lipopolysaccharide (LPS)- and TNF-alpha-induced apoptosis in bovine EC consistent with previous studies of human FADD. In contrast to human FADD, elevated expression of bovine FADD had no effect on LPS- or TNF-alpha-induced upregulation of NF-kappaB-dependent gene products as assayed by E-selectin expression. Thus, while the role of FADD in mediating apoptosis is conserved across species, its role in regulating NF-kappaB-dependent gene expression is not.