scholarly journals Mitochondrial Regulation of Cell Death: Mitochondria Are Essential for Procaspase 3-p21 Complex Formation To Resist Fas-Mediated Cell Death

1999 ◽  
Vol 19 (5) ◽  
pp. 3842-3847 ◽  
Author(s):  
Atsushi Suzuki ◽  
Yumi Tsutomi ◽  
Naoe Yamamoto ◽  
Tomoko Shibutani ◽  
Kouichi Akahane
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Complex Formation ◽  
Fas Ligand ◽  
Actinomycin D ◽  
Death Receptor ◽  
Mitochondrial Fraction ◽  
Functional Region ◽  
Mitochondrial Regulation ◽  
Cell Death Signaling

ABSTRACT Death receptor Fas transduces cell death signaling upon stimulation by Fas ligand, and this death signaling is mediated by caspase. Recently, we reported that the cell cycle regulator p21 interacts with procaspase 3 to resist Fas-mediated cell death. In the present study, the molecular characterization and functional region of the procaspase 3-p21 complex was further investigated. We observed the p21 expression in the mitochondrial fraction of HepG2 cells and detected Fas-mediated cell death only in the presence of actinomycin D. However, mitochondrial-DNA-lacking HepG2 (MDLH) cells showed this effect even in the absence of actinomycin D. Both p21 and procaspase 3 were expressed in MDLH cells, but the procaspase 3-p21 complex formation was not observed. Interestingly, the resistance to Fas-mediated cell death in the MDLH cells without actinomycin D was recovered after microinjection of HepG2-derived mitochondria into the MDLH cells. We conclude that mitochondria are necessary for procaspase 3-p21 complex formation and propose that the mitochondrial role during cell death is not only death induction but also death suppression.

scholarly journals sFasL—The Key to a Riddle: Immune Responses in Aging Lung and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2177
Author(s):  
Shulamit B. Wallach-Dayan ◽  
Dmytro Petukhov ◽  
Ronit Ahdut-HaCohen ◽  
Mark Richter-Dayan ◽  
Raphael Breuer
Keyword(s):  
Cell Death ◽  
Lung Disease ◽  
Fas Ligand ◽  
Death Receptor ◽  
Mesenchymal Cells ◽  
Soluble Form ◽  
Cell Accumulation ◽  
Key Factor ◽  
Aged Subjects

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL+ T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment.

Dephosphorylation of Fas-ligand and caveolin-1 is a prerequisite step in Fas-ligand - caveolin-1 complex formation and cell death stimulation

2020 ◽  
Vol 70 ◽  
pp. 109590
Author(s):  
Xenia A. Glukhova ◽  
Julia A. Trizna ◽  
Olga V. Proussakova ◽  
Vladimir G. Gogvadze ◽  
Igor P. Beletsky
Keyword(s):  
Cell Death ◽  
Complex Formation ◽  
Fas Ligand ◽  
Caveolin 1

scholarly journals Differentiating life and death: An inflammatory affair

2018 ◽  
Author(s):  
Dustin Lane
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Differentiation ◽  
Programmed Cell Death ◽  
Signaling Networks ◽  
Inhibitors Of Apoptosis ◽  
Life And Death ◽  
Cell Death Signaling ◽  
Cycle Dependent

Programmed cell death signaling networks are frequently activated to coordinate the process of cell differentiation, and a variety of apoptotic events can mediate the process. This can include the ligation of death receptors, the activation of downstream caspases, and the induction of chromatin fragmentation, and all of these events can occur without downstream induction of death. Importantly, regulators of programmed cell death also have established roles in mediating differentiation. This review will provide an overview of apoptosis and its regulation by Inhibitors of Apoptosis (IAPs) and Bcl-2 family members. It will then outline the cross-talk between NF-ĸB and apoptotic signaling in the regulation of apoptosis before discussing the function of these regulators in the control of cell differentiation. It will end on a discussion of how a DNA damage-directed, cell cycle-dependent differentiation program may be controlled across multiple passages through cell cycle, and will assert that the failure to properly differentiate is the underlying cause of cancer.

scholarly journals CD95/Fas ligand mRNA is toxic to cells

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Will Putzbach ◽  
Ashley Haluck-Kangas ◽  
Quan Q Gao ◽  
Aishe A Sarshad ◽  
Elizabeth T Bartom ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Fas Ligand ◽  
Death Receptor ◽  
Protein Translation ◽  
Similar Form ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Endogenous Protein ◽  
Critical Survival

CD95/Fas ligand binds to the death receptor CD95 to induce apoptosis in sensitive cells. We previously reported that CD95L mRNA is enriched in sequences that, when converted to si/shRNAs, kill all cancer cells by targeting critical survival genes (<xref ref-type="bibr" rid="bib27">Putzbach et al., 2017</xref>). We now report expression of full-length CD95L mRNA itself is highly toxic to cells and induces a similar form of cell death. We demonstrate that small (s)RNAs derived from CD95L are loaded into the RNA induced silencing complex (RISC) which is required for the toxicity and processing of CD95L mRNA into sRNAs is independent of both Dicer and Drosha. We provide evidence that in addition to the CD95L transgene a number of endogenous protein coding genes involved in regulating protein translation, particularly under low miRNA conditions, can be processed to sRNAs and loaded into the RISC suggesting a new level of cell fate regulation involving RNAi.

scholarly journals CD95/Fas ligand mRNA is toxic to cells

2018 ◽  
Author(s):  
William Putzbach ◽  
Ashley Haluck-Kangas ◽  
Quan Q. Gao ◽  
Aishe A. Sarshad ◽  
Elizabeth T. Bartom ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Fas Ligand ◽  
Death Receptor ◽  
Protein Translation ◽  
Similar Form ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Endogenous Protein ◽  
Critical Survival

AbstractCD95/Fas ligand binds to the death receptor CD95 to induce apoptosis in sensitive cells. We previously reported the CD95L mRNA is enriched in sequences that, when converted to si/shRNAs, kill all cancer cells by targeting critical survival genes (Putzbach et al., 2017). We now report expression of full-length CD95L mRNA, itself, is highly toxic to cells and induces a similar form of cell death. We demonstrate that small (s)RNAs derived from CD95L are loaded into the RNA induced silencing complex (RISC) RISC which is required for the toxicity and that processing of CD95L mRNA into sRNAs is independent of both Dicer and Drosha. We provide evidence that in addition to the CD95L transgene a number of endogenous protein coding genes involved in regulating protein translation, particularly under low miRNA conditions, can be processed to sRNAs and loaded into the RISC suggesting a new level of cell fate regulation involving RNAi.

scholarly journals Necrotic Death Pathway in FAS Receptor Signaling

2000 ◽  
Vol 151 (6) ◽  
pp. 1247-1256 ◽  
Author(s):  
Hirotaka Matsumura ◽  
Yusuke Shimizu ◽  
Yoshiyuki Ohsawa ◽  
Atsuo Kawahara ◽  
Yasuo Uchiyama ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Fas Ligand ◽  
Morphological Changes ◽  
Death Receptor ◽  
Jurkat Cells ◽  
Death Process ◽  
Pyrrolidine Dithiocarbamate ◽  
Death Domain ◽  
Cell Death Process

A caspase 8–deficient subline (JB6) of human Jurkat cells can be killed by the oligomerization of Fas-associated protein with death domain (FADD). This cell death process is not accompanied by caspase activation, but by necrotic morphological changes. Here, we show that the death effector domain of FADD is responsible for the FADD-mediated necrotic pathway. This process was accompanied by a loss of mitochondrial transmembrane potential (ΔΨm), but not by the release of cytochrome c from mitochondria. Pyrrolidine dithiocarbamate, a metal chelator and antioxidant, efficiently inhibited the FADD-induced reduction of ΔΨm and necrotic cell death. When human Jurkat, or its transformants, expressing mouse Fas were treated with Fas ligand or anti–mouse Fas antibodies, the cells died, showing characteristics of apoptosis. A broad caspase inhibitor (z-VAD–fmk) blocked the apoptotic morphological changes and the release of cytochrome c. However, the cells still died, and this cell death process was accompanied by a strong reduction in ΔΨm, as well as necrotic morphological changes. The presence of z-VAD–fmk and pyrrolidine dithiocarbamate together blocked cell death, suggesting that both apoptotic and necrotic pathways can be activated through the Fas death receptor.

scholarly journals Differentiating life and death: An inflammatory affair

2018 ◽  
Author(s):  
Dustin Lane
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Differentiation ◽  
Programmed Cell Death ◽  
Signaling Networks ◽  
Inhibitors Of Apoptosis ◽  
Life And Death ◽  
Cell Death Signaling ◽  
Cycle Dependent

Programmed cell death signaling networks are frequently activated to coordinate the process of cell differentiation, and a variety of apoptotic events can mediate the process. This can include the ligation of death receptors, the activation of downstream caspases, and the induction of chromatin fragmentation, and all of these events can occur without downstream induction of death. Importantly, regulators of programmed cell death also have established roles in mediating differentiation. This review will provide an overview of apoptosis and its regulation by Inhibitors of Apoptosis (IAPs) and Bcl-2 family members. It will then outline the cross-talk between NF-ĸB and apoptotic signaling in the regulation of apoptosis before discussing the function of these regulators in the control of cell differentiation. It will end on a discussion of how a DNA damage-directed, cell cycle-dependent differentiation program may be controlled across multiple passages through cell cycle, and will assert that the failure to properly differentiate is the underlying cause of cancer.

scholarly journals Cell polarity and adherens junction formation inhibit epithelial Fas cell death receptor signaling

2018 ◽  
Vol 217 (11) ◽  
pp. 3839-3852 ◽  
Author(s):  
Laurent Gagnoux-Palacios ◽  
Hala Awina ◽  
Stéphane Audebert ◽  
Aurélie Rossin ◽  
Magali Mondin ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Polarity ◽  
Fas Ligand ◽  
Death Receptor ◽  
Adherens Junction ◽  
Cellular Level ◽  
Protection Mechanism ◽  
Junction Formation ◽  
Additional Cell ◽  
E Cadherin

Finely tuned regulation of epithelial cell death maintains tissue integrity and homeostasis. At the cellular level, life and death decisions are controlled by environmental stimuli such as the activation of death receptors. We show that cell polarity and adherens junction formation prevent proapoptotic signals emanating from the Fas death receptor. Fas is sequestered in E-cadherin actin-based adhesion structures that are less able to induce downstream apoptosis signaling. Using a proteomic-based approach, we find that the polarity molecule Dlg1 interacts with the C-terminal PDZ-binding site in Fas and that this interaction decreases formation of the death-inducing complex upon engagement with Fas ligand (FasL), thus acting as an additional cell death protection mechanism. We propose that E-cadherin and Dlg1 inhibit FasL-induced cell death by two complementary but partially independent mechanisms that help to maintain epithelial homeostasis by protecting normal polarized epithelia from apoptosis. When polarity is lost, the Fas–cadherin–Dlg1 antiapoptotic complex is disrupted, and FasL can promote the elimination of compromised nonpolarized cells.

scholarly journals NF-κB Signals Induce the Expression of c-FLIP

2001 ◽  
Vol 21 (16) ◽  
pp. 5299-5305 ◽  
Author(s):  
Olivier Micheau ◽  
Susanne Lens ◽  
Olivier Gaide ◽  
Kostis Alevizopoulos ◽  
Jürg Tschopp
Keyword(s):  
Cell Death ◽  
Transcriptional Activation ◽  
Fas Ligand ◽  
Short Form ◽  
Death Receptor ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Alternatively Spliced ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT Activation of the transcription factor NF-κB is a major effector of the inducible resistance to death receptor-mediated apoptosis. Previous evidence indicates that the combined transcriptional activation of TRAF-1, TRAF-2, IAP-1, and IAP-2 is required to suppress cell death by tumor necrosis factor (TNF). Here we show that NF-κB activation upregulates the caspase 8 inhibitor FLIP, resulting in increased resistance to Fas ligand (FasL) or TNF. Restoration of either the full-length 55-kDa long form of FLIP or an alternatively spliced short form of FLIP in NF-κB null cells inhibits TNF- and FasL-induced cell death efficiently, whereas the expression of IAP or TRAF family members only partially rescues cells from death. Resistance to either FasL- or TNF-induced apoptosis is overcome when cells are incubated in the presence of the protein synthesis inhibitor cycloheximide. This treatment leads to the rapid downregulation of FLIP but not to that of TRAF2. Our findings suggest that FLIP is an important mediator of NF-κB-controlled antiapoptotic signals.

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