Death Receptors: Signaling and Modulation

Ashkenazi, Avi; Dixit, Vishva M.

doi:10.1126/science.281.5381.1305

Cited by 5,309 publications

(3,845 citation statements)

References 92 publications

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“…An insignificant decrease in CD95-positive cell population (44.0711.7%) was observed after a 24-h incubation with doxazosin at the lowest (20 a1-antagonist and expression pattern of TNF receptor in BPH patients T Drewa et al…”

Section: Resultsmentioning

confidence: 99%

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The influence of α1-antagonist on the expression pattern of TNF receptor family in primary culture of prostate epithelial cells from BPH patients

Drewa

Wolski

Misterek

et al. 2007

Prostate Cancer Prostatic Dis

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Doxazosin triggers apoptosis via an imprecisely defined receptor mechanism that is related to tumor necrosis factor receptors (TNFRs). The aim of this study was to determine CD95, TNFR-1, TNFR-2, CD40 expression in primary prostate epithelial cultures incubated with doxazosin. Epithelial cultures were cultivated from 10 benign prostate hyperplasia patients. The cells were incubated with 20, 50 and 80 lM of doxazosin. Apoptosis was confirmed by fluorescence microscopy and flow cytometry. The cells were analyzed for expression of FAS, CD40, TNFR-1 and TNFR-2 by flow cytometry. Early apoptotic cells were present in all groups. A positive correlation was noticed between doxazosin dose and TNFR-1-, -2-positive cells. A decrease of CD40-positive cell population was observed in the lowest concentration. A decrease of mean fluorescence intensity signal of CD40 and CD95 was observed in the lowest concentration. Doxazosin-triggered apoptosis was doseindependent. The initiation of apoptosis was a result of receptors 'crosstalk' rather than a single receptor pathway activation. TNF receptor self-assembly process should be checked as a potential mechanism leading to apoptosis after doxazosin treatment.

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Section: Resultsmentioning

confidence: 99%

“…It has been shown that TNFR-1 and TNFR-2 were able to mediate information for cell survival as well as apoptotic signals. [20][21][22] CD40 lacks a DD but can mediate both proapoptotic and antiapoptotic signals. 21 Trimerization is an active status of TNF family receptors.…”

Section: Introductionmentioning

confidence: 99%

The influence of α1-antagonist on the expression pattern of TNF receptor family in primary culture of prostate epithelial cells from BPH patients

Drewa

Wolski

Misterek

et al. 2007

Prostate Cancer Prostatic Dis

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“…Likewise, inner ear cells are also injured by the generation of free radicals and antioxidant depletion; they cause oxidative injury in the cochlea of the rat (Husain et al, 2001). The two major intracellular apoptosis pathways are the cell-surface death receptor or extrinsic pathway, that is, Fas and Tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated apoptosis, (involving procaspase-8 interactions) (Ashkenazi and Dixit, 1998), and the mitochondrion-initiated or intrinsic pathway, regulated by the members of the B-cell lymphoma 2 (Bcl-2) family (involving procaspase-9 interactions) (Harris and Thompson, 2000). Once activated, both caspases-8 and caspase-9 participate in a cascade that culminates in the activation of caspase-3 that cleaves several substrates, resulting in chromosomal DNA fragmentation and the cellular morphological changes characteristic of apoptosis (Goldstein et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

García-Berrocal

Nevado

Ramírez‐Camacho

et al. 2007

British J Pharmacology

106

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Background and purpose: Ototoxicity is a known adverse effect of cisplatin (CDDP). Since apoptosis is involved in the development of some pathological conditions associated with the administration of anticancer drugs, we examined, using immunohistochemical and electrophysiological techniques, the apoptotic changes in the cochlea of Sprague-Dawley (SD) rats after an injection of CDDP (5 mgkg -1 body weight). Experimental approach: Luciferase assays were used to determine the different caspase activities and ATP levels in protein extracts of whole cochleae. The expression of several apoptotic-related proteins was measured by means of Western blotting. These analyses were performed 2, 7 and 30 days after the CDDP injection. The auditory brain stem response was obtained before and at the different times after the injection of CDDP, before the animals were killed. Key results: CDDP significantly increased the levels of caspase-3/7 activity and active caspase-3 protein expression and caspase-3 immunofluorescence staining, caspase-9 activity, and Bax protein expression but decreased Bcl-2 protein expression within the rat cochleae. Threshold shifts were significantly elevated 2 days after CDDP treatment. Conclusions and implications: These findings support the hypothesis that cisplatin-related apoptosis evokes an intrinsic pathway of pro-apoptotic signalling within the rat cochleae. Thus, selective inhibition of the sequence of events involved in the intrinsic apoptotic pathway could provide a strategy to minimize cisplatin-induced ototoxicity.

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“…It forms two extracellular cysteine-rich, ligand-binding pseudorepeats (50s and 90s loops), a single transmembrane helix and a cytoplasmatic death domain that is able to engage the suicide machinery of cells and activate the apoptotic proteases to mediate apoptosis within a matter of hours. [4][5][6] It has been shown recently, that single amino acid mutations in wild-type TRAIL significantly changes the affinity of TRAIL toward its death receptor. 7 As both the single nucleotide polymorphisms (SNPs) analyzed within our study reside next to the DR4 ligand binding ectodomain, it might be speculated that they are likewise capable of modifying the TRAIL binding affinity.…”

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confidence: 99%

Association of death receptor 4 variant (683A>C) with ovarian cancer risk in BRCA1 mutation carriers

Dick

Versmold

Engel

et al. 2011

Intl Journal of Cancer

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Dysregulation of apoptosis plays an important role in carcinogenesis. Therefore, apoptosis-associated genes like the death receptor 4 (DR4, TRAIL-R1) are interesting candidates for modifying the penetrance of breast and ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The DR-4 haplotype 626C-683C [626C>G, Thr209Arg (rs4871857) and 683A>C, Glu228Ala (rs17088993)] has recently been linked to an increased risk of breast cancer. To evaluate whether DR4 626C>G or DR4 683A>C modifies the risk of breast or ovarian cancer in carriers of BRCA1 and BRCA2 mutations, we undertook a national multicenter study including data of 840 carriers of breast cancer gene (BRCA) mutations. DNA samples were collected from 12 German research centers between 1996 and 2005 and were genotyped by the Taqman allelic discrimination assay. The association between genotypes and incidence of breast or ovarian cancer data was evaluated using a Cox proportional hazards regression model. We found evidence for a significant association of DR4 683A>C with a higher risk for ovarian cancer in carriers of BRCA1 mutations [n 5 557, hazard ratio 1.78 (1.24-2.55), p 5 0.009]. Our results thus indicate that the DR4 683A>C variant modifies the risk of ovarian cancer in carriers of BRCA1 mutations.The transmembrane death receptors are members of the tumor necrosis factor (TNF) superfamily, characterized by their similar, cysteine-rich extracellular domains. 1 These receptors are involved in apoptosis, the programmed cell death, which keeps cell numbers and tissue sizes constant and is a critically important process during carcinogenesis. 2 As inactivation of the death receptors is expected to result in deficient apoptotic signaling 3 and thus in tumor growth, they are considered to be excellent candidate tumor suppressor genes.The TNF-related apoptosis-inducing ligand (TRAIL) binds to the proapoptotic death receptor 4 (DR4, TNFRSF10A, TRAIL-R1). 2 The DR4 gene is located on chromosome 8p21-22 and encodes 486 amino acids. It forms two extracellular cysteine-rich, ligand-binding pseudorepeats (50s and 90s loops), a single transmembrane helix and a cytoplasmatic death domain that is able to engage the suicide machinery of cells and activate the apoptotic proteases to mediate apoptosis within a matter of hours. [4][5][6] It has been shown recently, that single amino acid mutations in wild-type TRAIL significantly changes the affinity of TRAIL toward its death receptor. 7 As both the single nucleotide polymorphisms (SNPs) analyzed within our study reside next to the DR4 ligand binding

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Death Receptors: Signaling and Modulation

Cited by 5,309 publications

References 92 publications

The influence of α1-antagonist on the expression pattern of TNF receptor family in primary culture of prostate epithelial cells from BPH patients

The influence of α1-antagonist on the expression pattern of TNF receptor family in primary culture of prostate epithelial cells from BPH patients

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

Association of death receptor 4 variant (683A>C) with ovarian cancer risk in BRCA1 mutation carriers

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