Life and death by death receptors
ABSTRACT Death receptors are members of the tumor necrosis factor receptor superfamily characterized by a cytoplasmic region known as the "death domain" that enables the receptors to initiate cytotoxic signals when engaged by cognate ligands. Binding to the ligand results in receptor aggregation and recruitment of adaptor proteins, which, in turn, initiates a proteolytic cascade by recruiting and activating initiator caspases 8 and 10. Death receptors were once thought to primarily induce cytotoxic signaling cascades. However, recent data indicate that they initiate multiple signaling pathways, unveiling a number of nonapoptosis-related functions, including regulation of cell proliferation and differentiation, chemokine production, inflammatory responses, and tumor-promoting activities. These noncytotoxic cascades are not simply a manifestation of inhibiting proapoptotic pathways but are intrinsically regulated by adaptor protein and receptor internalization processes. Insights into these various death receptor signaling pathways provide new therapeutic strategies targeting these receptors in pathophysiological processes.
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- "Apoptosis is induced by two distinct, yet tightly interconnected signaling pathways: the extrinsic (Fig. 1) and the intrinsic (Fig. 2) apoptotic pathways. The extrinsic pathway is triggered by extracellular ligands such as those of the TNF superfamily (FasL, TNF␣ or TRAIL), which specifically bind to their respective surface receptors causing their oligomerization (Strasser et al., 2009; Guicciardi and Gores, 2009; Gonzalvez and Ashkenazi, 2010; Li et al., 2013a, 2013b). A conformational change on the cytoplasmic side of these receptors leads to the recruitment of the adapter protein FADD whose function is to attract pro-caspase-8 from the cytosol to the death receptor in order to bring two monomeric pro-caspase-8 molecules in close proximity for autoprocessing and subsequent activation (Fig. 1). "
ABSTRACT: There is no doubt that viruses require cells to successfully reproduce and effectively infect the next host. The question is what is the fate of the infected cells? All eukaryotic cells can"sense" viral infections and exhibit defence strategies to oppose viral replication and spread. This often leads to the elimination of the infected cells by programmed cell death or apoptosis. This"sacrifice" of infected cells represents the most primordial response of multicellular organisms to viruses. Subverting host cell apoptosis, at least for some time, is therefore a crucial strategy of viruses to ensure their replication, the production of essential viral proteins, virus assembly and the spreading to new hosts. For that reason many viruses harbor apoptosis inhibitory genes, which once inside infected cells are expressed to circumvent apoptosis induction during the virus reproduction phase. On the other hand, viruses can take advantage of stimulating apoptosis to (i) facilitate shedding and hence dissemination, (ii) to prevent infected cells from presenting viral antigens to the immune system or (iii) to kill non-infected bystander and immune cells which would limit viral propagation. Hence the decision whether an infected host cell undergoes apoptosis or not depends on virus type and pathogenicity, its capacity to oppose antiviral responses of the infected cells and/or to evade any attack from immune cells. Viral genomes have therefore been adapted throughout evolution to satisfy the need of a particular virus to induce or inhibit apoptosis during its life cycle. Here we review the different strategies used by viruses to interfere with the two major apoptosis as well as with the innate immune signaling pathways in mammalian cells. We will focus on the intrinsic mitochondrial pathway and discuss new ideas about how particular viruses could activately engage mitochondria to induce apoptosis of their host. Copyright © 2015. Published by Elsevier B.V.Virus Research 03/2015; 13. DOI:10.1016/j.virusres.2015.02.026 · 2.32 Impact Factor
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- "Here, the most extensively studied death ligands are type II transmembrane proteins, including FasL (for Fas receptor), TNF (for TNFR1 receptor), and TRAIL (for TRAIL receptor) [41, 42]. After proteolytic cleavage of the membrane-anchored ligand, these ligands are released from the plasma membrane and enable them to bind to death receptors and trigger their activation . Upon contacting with their corresponding ligands, these receptors are triggered, leading to the recruitment of a different set of adaptor molecules to the death domain and subsequent activation of the signaling cascade, where the major signals transmitted by death receptors such as Fas, TNFR1, TRAILR1, and TRAILR2 result in an apoptotic response mediated by intracellular caspases [43–48]. "
ABSTRACT: Cell death is a critical biological process, serving many important functions within multicellular organisms. Aberrations in cell death can contribute to the pathology of human diseases. Significant progress made in the research area enormously speed up our understanding of the biochemical and molecular mechanisms of cell death. According to the distinct morphological and biochemical characteristics, cell death can be triggered by extrinsic or intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Nevertheless, the realization that all of these efforts seek to pursue an effective treatment and cure for the disease have spurred a significant interests in the development of promising biomarkers of cell death to early diagnose disease and accurately predict disease progression and outcome. In this review, we summarize recent knowledge about cell death, survey current and emerging biomarkers of cell death and discuss the relationship with human diseases.BioMed Research International 04/2014; DOI:10.1155/2014/690103 · 2.71 Impact Factor
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- "TRAIL-R1(TNF-related apoptosis-inducing ligand receptor 1)/DR4 and Fas/Apo-1/CD95 are members of tumor necrosis factor receptors which link exogenous stimuli via transmembrane surface receptors to the intracellular signaling machinery that mediates and executes the death signal. These pathways are one of the major extrinsic apoptotic signaling pathway  and defects in death receptor signaling can confer resistance to apoptosis. The role of apoptosis in tumorigenesis has been well-documented  and resistance to apoptosis is believed to be a hallmark of cancer . "
ABSTRACT: Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4, FAS) and their ligands (TRAIL, FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis. Hence, the present study aimed to investigate the association of functional SNPs of DR4 (rs20575, rs20576 and rs6557634), FAS (rs2234767) and FASL (rs763110) with gallbladder cancer (GBC) risk. This case-control study included 400 GBC and 246 healthy controls (HC). Genotyping was carried out by Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) to systematically summarize the possible association of SNP with cancer risk. Functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). False discovery rate (FDR test) was used in multiple comparisons. The DR4 Crs20575Ars20576Ars6557634, Grs20575Ars20576Grs6557634 and Grs20575Crs20576Grs6557634 haplotypes conferred two-fold increased risk for GBC. Among these, the DR4 Crs20575Ars20576Ars6557634 haplotype emerged as main factor influencing GBC susceptibility as the risk was not modulated by gender or gallstone stratification. Our meta-analysis results showed significant association of DR4 rs6557634 with overall cancer risk, GI cancers as well as in Caucasians. We didn't find any association of FAS and FASL SNPs with GBC susceptibility. The DR4 haplotype Crs20575Ars20576Ars6557634 represents an important factor accounting the patients susceptibility to GBC probably due to decreased apoptosis. However, additional well-designed studies with larger sample size focusing on different ethnicities are required to further validate the results.PLoS ONE 02/2014; 9(2):e90264. DOI:10.1371/journal.pone.0090264 · 3.23 Impact Factor