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Apoptosis and Cell Death
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
In apoptosis signalling, receptor trimerization leads to recruitment of FADD (Fas-associated death domain), which binds the intracellular death domain (DD) portion of Fas, and procaspase 8 molecules bind to the death effector domain (DED) of FADD (Figure 6.2). Hence, procaspase 8 molecules are clustered and activated by autocleavage on a platform known as the death inducing signal complex (DISC). Trimerized receptors may also cluster into receptor microaggregates. In some cell types (type I cells), caspase 8 activation at the DISC is sufficient for downstream effector procaspase cleavage, but in many cell types (type II cells), the mitochondrial pathway is engaged to amplify the death signal by caspase 8-dependent cleavage of the BH3-only protein Bid, converting it to a form that is able to transmit the apoptotic signal to the mitochondrion. In addition, cytotoxic T cells release perforin, which penetrates the epithelial cell membrane, and granzyme B, a serine protease that can cleave and activate Bid, hence engaging the mitochondrial pathway.
Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Lixin Zheng, Richard M. Siegel, Jagan R. Muppidi, Felicita Hornung, Michael J. Lenardo
Death effector domains (DED) are interesting protein-interaction domains involved in apoptosis pathways. We have previously showed that overexpression of DED domains of FADD or caspase 8 causes formation of death filaments, which is well correlated with cell death.118 The mechanism of DED-induced cell death is not clear. One explanation is that when DED is overexpressed in cells, the homophilic association of DED may cause aggregation, which activates endogenous caspase-8 and/or -10. However, this hypothesis does not hold in certain circumstances. For example, there is evidence that the expression of human DED in bacteria causes bacterial death. It is unlikely that caspase activation is occurring in this case because no caspase homologue exists in bacterial genomes. Another explanation is that many overexpressed molecules can cause generic toxicity to host cells and that over expression of DEDs is just a trivial example of this phenomenon. This seems not to be the case in mammalian cells. Our recent data suggests that in caspase 8-deficient Jurkat T cells, the prodomains of caspase-8 and -10, each containing two DEDs, can mediate CD95-triggered, FADD-dependent cell death. Moreover, this cell death process is not inhibitable by the pan-caspase inhibitors zVAD and BocD, or by specific caspase 8/10 inhibitors such as IETD, DEVD, and zAEVD. Nevertheless, the RIP is required for this DED-mediated death signaling (Zheng and Lenardo, unpublished data). The involvement of RIP in an alternative pathway of CD95-death signals has been reported recently (Fig. 4).119 This alternative caspase-independent pathway of CD95-induced death and its physiological relevance are now under study. The biological significance of this new pathway of cell death largely depends on the confirmation of the existence of natural isoforms of caspase-8 and -10 that only contain the DEDs. Until now, these isoforms have been only observed at the mRNA level. Further work should establish if there is an alternative pathway of death receptor-mediated apoptosis, perhaps mediated by the DED-containing prodomains of caspase-8 and -10.
Chemical Causes of Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Gary M. Williams, Alan M. Jeffrey
Tumor cells can also acquire resistance to apoptosis or programmed cell death, which results from a variety of factors. For one, loss of matrix attachment leads to death of epithelial cells, a phenomenon termed anoikis (106). Also, a rapid process of apoptosis (2–8 hr) is evoked by various factors including extracellular factors such as tumor necrosis factor (TNF) family members, including TNF-α, Fas ligand (Fas L; also known as TNFSF6, tumor necrosis factor super family, member 6; APT1 APO1 or CD95) and TNF-related apoptosis-inducing ligand (TRAIL) (107), whereas a slower intrinsic process (8–48 hr) is mediated by intracellular factors such as proapoptotic products of the BCL-2 gene family (108). This slower form of apoptosis is initiated by mitochondrial release of proapoptotic factors and cytochrome C, which can result from translocation of BAX to mitochondria (109). Apoptosis is effected by caspases, which comprise three families of cysteine aspartate proteases (hence caspase) residing in the cyto-sol as inactive zymogens (110). Specific caspases are involved in either the initiation or execution phases of cell death. Members of one family, caspases 8 and 10, associate through a death effector domain with the cell membrane death receptors of TNF-α, Fas L or TRAIL. Another family of caspases, 1, 2, 4, 5, and 9, have a caspase recruiting domain. The downstream effector caspases are 3, 6, and 7, which are activated by members of the other two families. Deregulation of the death receptor pathway to apoptosis is frequent in many types of pediatric tumors due to methylation and gene silencing of CASP8 (111). Apoptosis can be inhibited by prevention of increased mitochondrial permeability transition and/or stabilization of the barrier function of the outer mitochondrial membrane (112) or through interaction with Apaf (apoptosis activation factor)-1 to inhibit activation of caspases (113). Antiapoptotic members of the BCL-2 gene family include BCL-2, BCL-XL, and MCL-1 which encode proteins that prevent release of proapoptotic factors, thereby conferring resistance to apoptosis. Because elevated expression of BCL-2 and BCL-XL results in enhanced cell survival, they are considered to be proto-oncogenes (Table 1a), although in some circumstances BCL-2 inhibits tumorigenesis (114). Inactivating mutations in the proapoptotic BAX and BAK genes are found in some cancers (115), and hence these are considered to be tumor suppressor genes (Table 1b). Another proapoptotic protein is death-associated protein (DAP) which is localized to the cytoskeleton and mediates interferon-γ-induced cell death (116). The gene for DAP kinase (DAPK1) is considered to be a tumor suppressor gene (Table 1b). Activation of RPTKs, including EGFR, ILGF-1R and Met, can alleviate anoikis (117). Overexpression of COX-2 can also inhibit apoptosis (118). Thus, tumor cells can acquire resistance to apoptosis through alteration of a number of signaling pathways, several of which are regulated by p53 (90).
Targeting of keloid with TRAIL and TRAIL-R2/DR5
Published in Journal of Dermatological Treatment, 2021
Pengfei Sun, Zhensheng Hu, Bo Pan, Xiaosheng Lu
In humans, TRAIL works by binding to five types of receptors, such as TRAIL-R1/death receptor (DR)4,TRAIL-R2/DR5,TRAIL-R3/DcR1,TRAIL-R4/DcR2,TRAIL-R5/Osteoprotegerin(OPG) (40) (Figure 2). Among them, TRAIL-R1/DR4 and TRAIL-R2/DR5 mediated apoptosis through cytoplasmic death domain (DD), but DD was incomplete or absent in TRAIL-R3/DcR1 and TRAIL-R4/DcR2, so it can not induce apoptosis. TRAIL-R5/OPG is a decoy receptor of TRAIL, which can inhibit apoptosis. AT the physiological conditions of cells, TRAIL is more inclined to interact with TRAIL-R2/DR5. Park et al. (41) proved that TRAIL-R2/DR5 is highly expressed in tumor cells, and its high expression can increase the sensitivity of TRAIL and increase the effect of inducing apoptosis of tumor cells. Therefore, TRAIL-R2/DR5 is more capable of mediating apoptosis and it is an important anticancer target. The specific process of action of TRAIL is that the ligand binds to the receptor (TRAIL-R1/DR4,TRAIL-R2/DR5), which activates the intracellular DD and binds to the C-terminal of the Fas related protein death domain (FADD) in the cytoplasm. The death response domain (DED) on the N-terminal of FADD is combined with the DED on Pro-Caspase8 to form the death-induced signal complex (DISC). Thus caspase-8 and caspase-10 were activated, and then downstream caspases 3, 6, 7 were activated, which resulted in apoptosis. In addition, caspase-8 promotes the release of cytochrome c and induced endophytic apoptosis of type II cells through mitochondrial pathway (42) (Figure 3).
Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Justyna Magdalena Hermanowicz, Anna Szymanowska, Beata Sieklucka, Robert Czarnomysy, Krystyna Pawlak, Anna Bielawska, Krzysztof Bielawski, Joanna Kalafut, Alicja Przybyszewska, Arkadiusz Surazynski, Adolfo Rivero-Muller, Mariusz Mojzych, Dariusz Pawlak
Stimulation of the extrinsic pathway starts with the activation of death receptors. After binding the appropriate death ligand, the receptors accumulate in clusters in the cell membrane and promote the recruitment of adapter proteins. These proteins have the death effector domain (DED), through which they interact with procaspase-8 and procaspase-10. The receptor, adapter protein, and procaspase form the complex DISC, that led to the activation of caspase-8 and caspase-10, and subsequently cell death. The activation of caspase-8 and caspase-10 was determined after 24-h treatment with RSC, 5-FU, and MM-129 by FLICA Caspase-8 Assay Kit (Supplementary Figure 3Sa, 3Sb) and FLICA Caspase-10 Assay Kit (Supplementary Figure 4Sa, 4Sb). It was shown that tested compound increased the expression of the active form of caspase-8 and caspase-10 in both cell lines. The highest percent of cells with the active form of caspase 8 was observed for MM-129 at a 3 µM concentration, and it was 81.2% on DLD-1 cell line and 67.8% on HT-29 cell (Figure 8(c,d)). Similar effect on the activation of caspase-10 in DLD-1 was also exhibited by MM-129 at a 3 µM concentration; the percentage of cells with the active form of initiator caspase-10 was 42.9%. The highest percentage of HT-29 cells expressing active caspase-10 was also evoked by compound MM-129, and it was 37.9% (Figure 8(e,f)).
TIPE2 as a potential therapeutic target in chronic viral hepatitis
Published in Expert Opinion on Therapeutic Targets, 2019
Jian Ji, Yuan-Yuan Zhang, Yu-Chen Fan
The sequence of TNFAIP8 contains a putative death effector domain (DED) that shows significant homology with DED II of the Fas-associated death domain-like interleukin-1β-converting enzyme-inhibitory protein (FLIP) family [29]. TNFAIP8 is believed to exhibit anti-apoptotic activity.TIPE2 comprises a predicted open reading frame encoding 184 amino acids and a putative human TIPE2 homolog shares 94.0% amino acid sequence identity and 96.7% similarity with mouse TIPE2. In Figure 1, we show that human TIPE2 shares approximately 50.0% identity and 71.7% similarity with humanTNFAIP8, 57.0 identify and 74.7% similarity with human TIPE1, as well as 34.6% identity and 49.3 similarity with human TIPE3 (Figure 1). Additionally, TIPE2 exhibits an unusual feature – a centrally located, large hydrophobic cavity [30]. The central cavity plays an important role in the maintenance of immune homeostasis by binding to a cofactor. Experimental evidence indicates that TIPE2 contains a putative DED-like domain that shows significant identity to other known DED sequences. It is now well accepted that certain DED-containing proteins are capable of regulating apoptosis in addition to cell activation. These proteins include the Fas-associated death domain (FADD) [31], FLIP, and caspase-8 protein.