Cell Death

Journal of Neurochemistry, 2007

Optic nerve transection results in the death of retinal ganglion cells (RGCs) by apoptosis. Apoptosis is regulated by the Bcl-2 family of proteins, of which the Bcl-2 homology (BH3) -only proteins forms a subset. As BH3-only proteins have been shown to play a significant role in regulating cell death in the central nervous system, we wished to investigate the role of Bcl-2 interacting mediator of cell death (Bim), a prominent member of this protein family in the regulation of cell death in the RGC layer using in vitro retinal explants. In this study, we use an innovative retinal shaving procedure to isolate the cells of the ganglion cell layer to use for western blotting. Members of the BH3-only protein family are down-regulated during retinal development and are not normally expressed in the adult retina. Using this procedure, we demonstrate that Bim is re-expressed and its expression is increased over time following axotomy. Expression of Bad and Bik decreases over the same time course, whereas there is no indication that Bid and Puma are re-expressed. We show that explants from Bim knockout mice are resistant to axotomy-induced death when compared with their wild-type counterparts. Genetic deletion of Bim also prevents caspase 3 cleavage. The activity of Bim can be negatively regulated by phosphorylation. We show that the decrease of Bim phosphorylation correlates with a decrease in expression of survival kinases such as pAkt and pERK over the same time course. These results implicate Bim re-expression as being essential for axotomy-induced death of RGCs and that phosphorylation of Bim negatively regulates its activity in RGCs.

Annals of the New York Academy of Sciences, 2006

A BSTRACT : Apoptosis is an evolutionarily conserved process for killing unwanted cells. Genetic and biochemical experiments have indicated that three groups of proteins are necessary for activation of the cell-death effector machinery: cysteine proteases, their adaptors, and proapoptotic Bcl-2 family members. Antiapoptotic Bcl-2 family members are needed for cell survival. We have cloned Bim, a proapoptotic Bcl-2 family member that shares with the family only a 9-16 aa region of homology [Bcl-3 homology region(BH3)], but is otherwise unique. Bim requires its BH3 region for binding to Bcl-2 and activation of apoptosis. Analysis of Bim-deficient mice has shown that Bim is essential for the execution of some but not all apoptotic stimuli that can be antagonized by Bcl-2. Bim-deficient mice have increased numbers of lymphocytes, plasma cells, and myeloid cells, and most develop fatal autoimmune glomerulonephritis. In healthy cells, Bim is bound to the microtubule-associated dynein motor complex, and is thereby sequestered from Bcl-2. Certain apoptotic signals unleash Bim and allow it to translocate to intracellular membranes, where it interacts with Bcl-2 or its homologues. These results indicate that BH3-only proteins are essential inducers of apoptosis that can be unleashed by certain death signals. Unleashed BH3-only proteins neutralize the prosurvival function of Bcl-2-like molecules, and this is thought to liberate Apaf-l-like adapters to activate caspase zymogens, which then initiate cell degradation.

Indian Journal of Veterinary Pathology, 2023

Cell death is vital in embryonic development, tissue molding during embryogenesis, immune system development and removal of damaged cells. However, subsequent release of various infl ammatory cytokines intracellularly leads to infl ammatory changes during necrosis, pyroptosis and necroptosis. Necroptosis is regulated cell death with mimicking feature of apoptosis and necrosis. In NETosis and ferroptosis, reactive oxygen species leads to the oxidative cell death. In pyroptosis, caspase-1 enzyme release pro-infl ammatory molecules which lead to infl ammatory changes.

Apoptosis, 2012

Necroptosis is a physiologically relevant mode of cell death with some well-described initiating events, but largely unknown executioners. Here we investigated necrostatin-1 (Nec-1) sensitive death elicited by different necroptosis stimuli in L929 mouse fibrosarcoma cells, mouse embryonic fibroblasts (MEF) and bone marrow-derived macrophages. We found that TNFαor zVAD-induced necroptosis occurs independently of the recently implicated executioners Bmf or PARP-2, but can involve the Bcl-2 family proteins Bid and Bak.

The National medical journal of India

Apoptosis is a programmed and controlled form of cell death, which is distinct from necrosis. It is a non-inflammatory process and plays an important role in numerous physiological and pathological events. It has an indispensable role in the development and homeostasis in tissues of all higher organisms. Apoptosis can be identified by various methods such as electron microscopy, agarose gel electrophoresis, deoxyribonucleic acid fragmentation analysis, Tdt-dUTP terminal nick end labelling (TUNEL) assay, flow cytometry, annexin V staining and enzyme assays. A number of genes have been identified which are involved in this process. Many approaches for the control of apoptosis are being developed from the understanding of its molecular mechanisms. These include pharmacological inhibition or overexpression of the involved genes, gene therapy by viral transduction of apoptotic inhibitors, inhibition of proteases, inhibition of intracellular rise in calcium concentration and inhibition by...

Annual review of cell and developmental biology, 2014

Cell turnover is a fundamental feature in metazoans. Cells can die passively, as a consequence of severe damage to their structural integrity, or actively, owing to a more confined biological disruption such as DNA damage. Passive cell death is uncontrolled and often harmful to the organism. In contrast, active cell death is tightly regulated and serves to support the organism's life. Apoptosis-the primary form of regulated cell death-is relatively well defined. Necroptosis-an alternative, distinct kind of regulated cell death discovered more recently-is less well understood. Apoptosis and necroptosis can be triggered either from within the cell or by extracellular stimuli. Certain signaling components, including several death ligands and receptors, can regulate both processes. Whereas apoptosis is triggered and executed via intracellular proteases called caspases, necroptosis is suppressed by caspase activity. Here we highlight current understanding of the key signaling mechani...

Cell death and differentiation, 2018

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The miss...

Current Molecular Biology Reports

One of the vital aspects of a cell is cell death to continue their normal cell turnover, propagation, proper development, and the maintenance of the immune system. Cell death is an essential process in the body as it promotes the removal of unwanted cells. It is the programmed culling of cells in entire eukaryotic development processes to survive and progress for the next generation. Molecular aberration in the process of apoptosis may have pathological manifestations, including cancer, neurodegenerative disorders, autoimmune disease, and ischemic damage. Classically, cell death is categorized primarily into four different types: apoptosis, autophagy, necrosis, and entosis; depending on cellular and molecular signatures governing the pathway involved. The purpose of this review is to compare and contrast the recent literature on cell death and to familiarize with the current state of knowledge on this topic. In summary, the hallmarks of various modes of cell death are thoroughly explained along with the other types of cell death such as ferroptosis, pyroptosis, necroptosis, and lysosomal-dependent cell death.

Rheumatic diseases clinics of North America, 2004

The understanding of the apoptotic program has grown exponentially over the past decade. Numerous human diseases have been directly linked to genetic defects in the apoptotic pathways, including cancer, neurodegenerative disorders, and autoimmune diseases. Caspases initiate and amplify various death signals, allowing for selective and ordered cellular demolition. The fine balance between pro- and antiapoptotic Bcl-2 family members regulates the cell fate in response to many (but not all) stress or signaling pathways. Recent discoveries highlight the complex integration of signals from various organelles that determine cell fate and the multiple functions of central players in the apoptotic process. It is likely that the knowledge obtained in a relatively time will translate into better diagnostics and therapies to enhance or retard cell death in the appropriate clinical circumstances.

Asian Journal of Animal and Veterinary Advances, 2015

The normal cell has its own homeostatic mechanism. A slight deviation in this mechanism leads firstly to an adaptive response in the form of hypertrophy, atrophy etc. But sometimes when adaptive response exceeds a limit also culminates to cell injury which ultimately leads to cell death. Irreversible form of cell injury leads to cell death in the form of necrosis, apoptosis and autophagy and by other alternative ways of necroptosis, anoikis, entosis and cornification. Necrosis and apoptosis are main mechanisms of cell death in mammalian cells. Necrosis is accidental, uncontrolled and un-programmed cell death which leads to cellular swelling, pyknosis, karyolysis, karyorrhexis, disruption of cell membrane and inflammation. Apoptosis is a programmed and energy dependent pathophysiological phenomenon leading to cellular shrinkage but no cell membrane rupture and no inflammatory response. Apoptosis can be mediated by extrinsic, intrinsic and perforin/granzyme pathways, leading to activation of execution caspases and finally protein cleavage, cross linking and DNA-fragmentation. Extrinsic pathway involve ligand (FasL, TNFα) and receptors (FasR, TNFR) interaction which bind to adapter proteins Fas Associated Death Domain (FADD) and TNFα Receptor Associated Death Domain (TRADD) with activation of initiator caspases-8. Intrinsic pathway involves cytochrome c release along with pro-apoptotic proteins and inhibits anti-apoptotic proteins, leads to cytochrome c interaction with Apaf-1, thus activation of pro-caspase-9. Overall, cell death have clarified many aspects of this fundamental process and brought to the attention of scientists its role in a large number of different diseases. The present review describes apoptosis and other alternate mechanisms of cell death with biomedical and veterinary perspectives.