F-actin as a functional target for retro-retinoids: a potential role in anhydroretinol-triggered cell death

The retro-retinoids, metabolites of vitamin A (retinol), belong to a family of lipophilic signalling molecules implicated in regulation of cell growth and survival. Growth-promoting properties have been ascribed to 14-hydroxy-retro-retinol (14HRR), while anhydroretinol (AR) was discovered to act as a natural antagonist triggering growth arrest and death by apoptosis. Based on morphological studies and inhibition of apoptosis by the kinase blocker, herbimycin A, it has been suggested that retro-retinoids exhibit their function in the cytosolic compartment. F-actin emerged as a functional target for retro-retinoid action. By FACS analysis and fluorescence microscopy of phalloidin-FITC labeled cells we demonstrated that F-actin reorganization was an early event in AR-triggered apoptosis. Fluorescence images of AR-treated fibroblasts displayed short, thick, stick-like and punctate structures, and membrane ruffles at the cell periphery along with an increased diffuse staining pattern. Reversal of the AR effect by 14HRR or retinol indicates that F-actin is a common site for regulation by retro-retinoids. Inhibition of both cell death and actin depolymerisation by bcl-2 implies that cytoskeleton reorganization is downstream of bcl-2-related processes. Furthermore, stabilization of microfilaments by jasplakinolide increased the survival potential of AR treated cells, while weakening the cytoskeleton by cytochalasin B abetted apoptosis. Thus the cytoskeleton is an important way station in a communication network that decides whether a cell should live or die.

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The mechanism of T cell mediated cytotoxicity V. Morphological studies by electron microscopy

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1977.0100 ◽

1977 ◽

Vol 198 (1132) ◽

pp. 315-323 ◽

Cited By ~ 32

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Target Cell ◽

Plasma Membranes ◽

Ultrastructural Changes ◽

Early Event ◽

Target Cells ◽

Cell Functions ◽

Morphological Studies

The ultrastructural changes occurring when T cells specifically immune to antigens interact with P815 mastocytoma cells and EL4 lymphoma cells are described and related to changes previously observed by timelapse cinematography (Sanderson 1976 b ). In confirmation of work by others, pale T cells can clearly be incriminated as cytotoxic cells. Dark T cells also form contacts with target cells, and tend to project lamellipodia over the surface of the target cell. The possibility is discussed that these represent a subset of non-cytotoxic, antigen-reactive T cells involved in other T cell functions. T cells form two types of contact: relatively small point contacts, and large areas where the two plasma membranes are in close apposition. No structures resembling specialized junctions or membrane fusions were observed in areas of contact between T cells and target cells. Close contact between pale T cells and target cells is more regular than contact with dark T cells. Many contacts were seen between morphologically normal target cells and pale T cells, and these were thought to occur in the phase between contact and target cell death. Some of these pale T cells in contact show projections towards the centre of the target cell which invaginate the cell membrane, but do not penetrate it. Remarkable T cell projections were also seen which had penetrated deeply through the membrane of one target cell. These projections appeared to have disrupted the membrane and had penetrated into apparently intact cytoplasm, suggesting that this penetration may be an early event in the lytic mechanism. The possibility that this phenomenon is the cause of cell death is discussed. Changes corresponding to the phase of zeiosis of the target cell are described. These commence with the formation of surface blebs, accompanied by a general mis-shapening of the cell outline and followed by vacuolation and loss of cytoplasmic organelles. Breakdown of the nucleus appears to be a later, post mortem event.

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Molecular characterization of a fungal gasdermin-like protein

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2004876117 ◽

2020 ◽

Vol 117 (31) ◽

pp. 18600-18607 ◽

Cited By ~ 3

Author(s):

Asen Daskalov ◽

Patrick S. Mitchell ◽

Andrew Sandstrom ◽

Russell E. Vance ◽

N. Louise Glass

Keyword(s):

Cell Death ◽

Cellular Localization ◽

Defense Mechanism ◽

Evolutionary Relationship ◽

Cell Periphery ◽

Dependent Cell ◽

A Cell ◽

Necessary And Sufficient ◽

Relationship Of

Programmed cell death (PCD) in filamentous fungi prevents cytoplasmic mixing following fusion between conspecific genetically distinct individuals (allorecognition) and serves as a defense mechanism against mycoparasitism, genome exploitation, and deleterious cytoplasmic elements (i.e., senescence plasmids). Recently, we identifiedregulatorof cell death-1(rcd-1), a gene controlling PCD in germinated asexual spores in the filamentous fungusNeurospora crassa.rcd-1alleles are highly polymorphic and fall into two haplogroups inN. crassapopulations. Coexpression of alleles from the two haplogroups,rcd-1–1andrcd-1–2, is necessary and sufficient to trigger a cell death reaction. Here, we investigated the molecular bases ofrcd-1-dependent cell death. Based on in silico analyses, we found that RCD-1 is a remote homolog of the N-terminal pore-forming domain of gasdermin, the executioner protein of a highly inflammatory cell death reaction termed pyroptosis, which plays a key role in mammalian innate immunity. We show that RCD-1 localizes to the cell periphery and that cellular localization of RCD-1 was correlated with conserved positively charged residues on predicted amphipathic α-helices, as shown for murine gasdermin-D. Similar to gasdermin, RCD-1 binds acidic phospholipids in vitro, notably, cardiolipin and phosphatidylserine, and interacts with liposomes containing such lipids. The RCD-1 incompatibility system was reconstituted in human 293T cells, where coexpression of incompatiblercd-1–1/rcd-1–2alleles triggered pyroptotic-like cell death. Oligomers of RCD-1 were associated with the cell death reaction, further supporting the evolutionary relationship between gasdermin andrcd-1. This report documents an ancient transkingdom relationship of cell death execution modules involved in organismal defense.

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Harpin and hydrogen peroxide both initiate programmed cell death but have differential effects on defence gene expression in Arabidopsis suspension cultures

Biochemical Journal ◽

10.1042/bj3300115 ◽

1998 ◽

Vol 330 (1) ◽

pp. 115-120 ◽

Cited By ~ 234

Author(s):

Radhika DESIKAN ◽

Adele REYNOLDS ◽

T. John HANCOCK ◽

J. Steven NEILL

Keyword(s):

Gene Expression ◽

Cell Death ◽

Programmed Cell Death ◽

Plant Defence ◽

Suspension Cultures ◽

Ros Generation ◽

Resistance Response ◽

Signalling Molecules ◽

Cell Death Pathway ◽

A Cell

Programmed cell death is increasingly viewed as a key component of the hypersensitive disease resistance response of plants. The generation of reactive oxygen species (ROS) such as H2O2 triggers a cell death programme in Arabidopsis suspension cultures following challenge with the bacterial elicitor harpin. Both harpin and exogenous H2O2 initiate a cell death pathway that requires gene expression, and also act as signalling molecules to induce the expression of plant defence genes encoding enzymes such as phenylalanine ammonia-lyase (PAL), glutathione S-transferase (GST) and anthranilate synthase (ASA1), an enzyme of phytoalexin biosynthesis in Arabidopsis. H2O2 induces the expression of PAL1 and GST but not that of ASA1. Harpin initiates two signalling pathways, one leading to increased ROS generation and expression of PAL1 and GST mRNA, and another leading to increased GST and ASA1 expression, independent of H2O2.

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A Cell Death Pathway Induced by Antibody-Mediated Cross-Linking of CD45 on Lymphocytes

Critical Reviews in Immunology ◽

10.1615/critrevimmunol.v23.i56.40 ◽

2003 ◽

Vol 23 (5-6) ◽

pp. 421-440 ◽

Cited By ~ 9

Author(s):

Ann-Muriel Steff ◽

Marylene Fortin ◽

Fabianne Philippoussis ◽

Sylvie Lesage ◽

Chantal Arguin ◽

...

Keyword(s):

Cell Death ◽

Cross Linking ◽

Cell Death Pathway ◽

A Cell

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Mitochondria and Pharmacologic Cardiac Conditioning—At the Heart of Ischemic Injury

International Journal of Molecular Sciences ◽

10.3390/ijms22063224 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3224

Author(s):

Christopher Lotz ◽

Johannes Herrmann ◽

Quirin Notz ◽

Patrick Meybohm ◽

Franz Kehl

Keyword(s):

Cell Death ◽

Mitochondrial Permeability Transition ◽

Permeability Transition ◽

Research Field ◽

Calcium Handling ◽

Control Mechanisms ◽

Intrinsic Resistance ◽

Atp Production ◽

Cardiac Conditioning ◽

A Cell

Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.

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Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0530113100 ◽

2003 ◽

Vol 100 (5) ◽

pp. 2825-2830 ◽

Cited By ~ 59

Author(s):

J. Niquet ◽

R. A. Baldwin ◽

S. G. Allen ◽

D. G. Fujikawa ◽

C. G. Wasterlain

Keyword(s):

Cell Death ◽

Protein Synthesis ◽

Neuronal Necrosis ◽

Cell Death Program ◽

A Cell

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Identification of Selenoprotein P Fragments as a Cell-Death Inhibitory Factor

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.26.794 ◽

2003 ◽

Vol 26 (6) ◽

pp. 794-798 ◽

Cited By ~ 12

Author(s):

Masaki Hirashima ◽

Takeshi Naruse ◽

Hiroaki Maeda ◽

Chikateru Nozaki ◽

Yoshiro Saito ◽

...

Keyword(s):

Cell Death ◽

Inhibitory Factor ◽

Selenoprotein P ◽

A Cell

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Increased cell death in osteopontin-deficient cardiac fibroblasts occurs by a caspase-3-independent pathway

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00098.2004 ◽

2004 ◽

Vol 287 (4) ◽

pp. H1730-H1739 ◽

Cited By ~ 37

Author(s):

Ron Zohar ◽

Baoqian Zhu ◽

Peter Liu ◽

Jaro Sodek ◽

C. A. McCulloch

Keyword(s):

Cell Death ◽

Caspase 3 ◽

Cardiac Fibroblasts ◽

Chromatin Condensation ◽

Terminal Deoxynucleotidyl Transferase ◽

Tunel Staining ◽

Wild Type ◽

Nuclear Fragmentation ◽

A Cell

Reperfusion-induced oxidative injury to the myocardium promotes activation and proliferation of cardiac fibroblasts and repair by scar formation. Osteopontin (OPN) is a proinflammatory cytokine that is upregulated after reperfusion. To determine whether OPN enhances fibroblast survival after exposure to oxidants, cardiac fibroblasts from wild-type (WT) or OPN-null (OPN−/−) mice were treated in vitro with H2O2to model reperfusion injury. Within 1 h, membrane permeability to propidium iodide (PI) was increased from 5 to 60% in OPN−/−cells but was increased to only 20% in WT cells. In contrast, after 1–8 h of treatment with H2O2, the percent of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-stained cells was more than twofold higher in WT than OPN−/−cells. Electron microscopy of WT cells treated with H2O2showed chromatin condensation, nuclear fragmentation, and cytoplasmic and nuclear shrinkage, which are consistent with apoptosis. In contrast, H2O2-treated OPN−/−cardiac fibroblasts exhibited cell and nuclear swelling and membrane disruption that are indicative of cell necrosis. Treatment of OPN−/−and WT cells with a cell-permeable caspase-3 inhibitor reduced the percentage of TUNEL staining by more than fourfold in WT cells but decreased staining in OPN−/−cells by ∼30%. Although the percentage of PI-permeable WT cells was reduced threefold, the percent of PI-permeable OPN−/−cells was not altered. Restoration of OPN expression in OPN−/−fibroblasts reduced the percentage of PI-permeable cells but not TUNEL staining after H2O2treatment. Thus H2O2-induced cell death in OPN-deficient cardiac fibroblasts is mediated by a caspase-3-independent, necrotic pathway. We suggest that the increased expression of OPN in the myocardium after reperfusion may promote fibrosis by protecting cardiac fibroblasts from cell death.

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