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Structure (London, England : 1993) Apr 2013Apaf-1-like molecules assemble into a ring-like platform known as the apoptosome. This cell death platform then activates procaspases in the intrinsic cell death... (Review)
Review
Apaf-1-like molecules assemble into a ring-like platform known as the apoptosome. This cell death platform then activates procaspases in the intrinsic cell death pathway. In this review, crystal structures of Apaf-1 monomers and CED-4 dimers have been combined with apoptosome structures to provide insights into the assembly of cell death platforms in humans, nematodes, and flies. In humans, the caspase recognition domains (CARDs) of procaspase-9 and Apaf-1 interact with each other to form a CARD-CARD disk, which interacts with the platform to create an asymmetric proteolysis machine. The disk tethers multiple pc-9 catalytic domains to the platform to raise their local concentration, and this leads to zymogen activation. These findings have now set the stage for further studies of this critical activation process on the apoptosome.
Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Apoptosomes; Apoptotic Protease-Activating Factor 1; Caenorhabditis elegans; Calcium-Binding Proteins; Caspase 9; Dimerization; Drosophila; Enzyme Activation; Humans; Models, Molecular; Protein Conformation; Species Specificity
PubMed: 23561633
DOI: 10.1016/j.str.2013.02.024 -
Development (Cambridge, England) Jul 2020Cell death is an important facet of animal development. In some developing tissues, death is the ultimate fate of over 80% of generated cells. Although recent studies... (Review)
Review
Cell death is an important facet of animal development. In some developing tissues, death is the ultimate fate of over 80% of generated cells. Although recent studies have delineated a bewildering number of cell death mechanisms, most have only been observed in pathological contexts, and only a small number drive normal development. This Primer outlines the important roles, different types and molecular players regulating developmental cell death, and discusses recent findings with which the field currently grapples. We also clarify terminology, to distinguish between developmental cell death mechanisms, for which there is evidence for evolutionary selection, and cell death that follows genetic, chemical or physical injury. Finally, we suggest how advances in understanding developmental cell death may provide insights into the molecular basis of developmental abnormalities and pathological cell death in disease.
Topics: Animals; Apoptosis; Apoptosomes; Autophagy; Caspases; Cell Death; Gene Expression Regulation, Developmental; Invertebrates; Mammals; Signal Transduction
PubMed: 32709690
DOI: 10.1242/dev.191882 -
Apoptosis : An International Journal on... Nov 2004Apoptosis is a cell suicide mechanism that enables organisms to control cell number and eliminate cells that threaten survival. The apoptotic cascade can be triggered... (Review)
Review
Apoptosis is a cell suicide mechanism that enables organisms to control cell number and eliminate cells that threaten survival. The apoptotic cascade can be triggered through two major pathways. Extracellular signals such as members of the tumor necrosis factor (TNF) family can activate the receptor-mediated extrinsic pathway. Alternatively, stress signals such as DNA damage, hypoxia, and loss of survival signals may trigger the mitochondrial intrinsic pathway. In the latter, mitochondrial damage results in cytochrome c release and formation of the apoptosome, a multimeric protein complex containing Apaf-1, cytochrome c , and caspase-9. Once bound to the apoptosome, caspase-9 is activated, and subsequently triggers a cascade of effector caspase activation and proteolysis, leading to apoptotic cell death. Recent efforts have led to the identification of multiple factors that modulate apoptosome formation and function. Alterations in the expression and/or function of these factors may contribute to the pathogenesis of cancer and resistance of tumor cells to chemotherapy or radiation. In this review we discuss how disruption of normal apoptosome formation and function may lead or contribute to tumor development and progression.
Topics: Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Caspases; Cytochrome c Group; Enzyme Activation; Humans; Mitochondria; Models, Biological; Neoplasms; Proteins; Tumor Necrosis Factors
PubMed: 15505412
DOI: 10.1023/B:APPT.0000045786.98031.1d -
Oncotarget Apr 2017As the most intensively studied initiator caspase, caspase-9 is a key player in the intrinsic or mitochondrial pathway which is involved in various stimuli, including... (Review)
Review
As the most intensively studied initiator caspase, caspase-9 is a key player in the intrinsic or mitochondrial pathway which is involved in various stimuli, including chemotherapies, stress agents and radiation. Caspase-9 is activated on the apoptosome complex to remain catalytic status and is thought of involving homo-dimerization monomeric zymogens. Failing to activate caspase-9 has profound physiological and pathophysiological outcomes, leading to degenerative and developmental disorders even cancer. To govern the apoptotic commitment process appropriately, plenty of proteins and small molecules involved in regulating caspase-9. Therefore, this review is to summarize recent pertinent literature on the comprehensive description of the molecular events implicated in caspase-9 activation and inhibition, as well as the clinical trials in progress to give deep insight into caspase-9 for suppressing cancer. We hope that our concerns will be helpful for further clinical studies addressing the roles of caspase-9 and its regulators demanded to identify more effective solutions to overcome intrinsic apoptosis-related diseases especially cancer.
Topics: Animals; Apoptosis; Caspase 9; Humans; Phosphorylation; Signal Transduction
PubMed: 28177918
DOI: 10.18632/oncotarget.15098 -
Cell Death and Differentiation Jan 2012Deregulation of innate immune signalling and cell death form the basis of most human disease pathogenesis. Inhibitor of APoptosis (IAP) protein-family members are... (Review)
Review
Deregulation of innate immune signalling and cell death form the basis of most human disease pathogenesis. Inhibitor of APoptosis (IAP) protein-family members are frequently overexpressed in cancer and contribute to tumour cell survival, chemo-resistance, disease progression and poor prognosis. Although best known for their ability to regulate caspases, IAPs also influence ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-κB. Recent advances in our understanding of the molecular mechanisms through which IAPs influence cell death and innate immune responses have provided new insights into novel strategies for treatment of cancer. In this review we discuss our current understanding of IAP-mediated NF-κB signalling, as well as elaborate on unexpected insights into the involvement of IAPs in regulating the 'Ripoptosome', a novel intrinsic cell death-inducing platform. We propose an evolutionarily conserved concept whereby IAPs function as guardians of killer platforms such as the apoptosome in Drosophila and the Ripoptosome in mammals.
Topics: Animals; Apoptosis; Caspases; Drosophila; Humans; Inhibitor of Apoptosis Proteins; NF-kappa B; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction; Tumor Necrosis Factor-alpha; Ubiquitin
PubMed: 22095281
DOI: 10.1038/cdd.2011.163 -
Journal of Personalized Medicine Aug 2022To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the... (Review)
Review
To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.
PubMed: 36013278
DOI: 10.3390/jpm12081329 -
Annals of the New York Academy of... Jul 2010Mitochondrial bioenergetic function is a key to cell life and death. Cells need energy not only to support their vital functions but also to die gracefully. Execution of... (Review)
Review
Mitochondrial bioenergetic function is a key to cell life and death. Cells need energy not only to support their vital functions but also to die gracefully. Execution of an apoptotic program includes energy-dependent steps, including kinase signaling, formation of the apoptosome, and effector caspase activation. Under conditions of bioenergetic collapse, cells are diverted toward necrotic demise. Mitochondrial outer membrane permeabilization (MOMP) is a decisive event in the execution of apoptosis. It is also causally linked to a decline in bioenergetic function via different mechanisms, not merely due to cytochrome c dispersion. MOMP-induced bioenergetic deficiency is usually irreversible and commits cells to die, even when caspases are inactive. Here, we discuss the mechanisms by which MOMP impacts bioenergetics in different cell death paradigms.
Topics: Apoptosis; Caspases; Cell Death; Cell Survival; Cytochromes c; Energy Metabolism; Enzyme Activation; HeLa Cells; Humans; Mitochondria; Mitochondrial Membranes; NAD; Necrosis; Oxygen; bcl-2-Associated X Protein
PubMed: 20649539
DOI: 10.1111/j.1749-6632.2010.05633.x -
Neoplasia (New York, N.Y.) Apr 1999Apoptosis is a fundamental biologic process by which metazoan cells orchestrate their own self-demise. Genetic analyses of the nematode C elegans identified three core... (Review)
Review
Apoptosis is a fundamental biologic process by which metazoan cells orchestrate their own self-demise. Genetic analyses of the nematode C elegans identified three core components of the suicide apparatus which include CED-3, CED-4, and CED-9. An analogous set of core constituents exists in mammalian cells and includes caspase-9, Apaf-1, and bcl-2/xL, respectively. CED-3 and CED-4, along with their mammalian counterparts, function to kill cells, whereas CED-9 and its mammalian equivalents protect cells from death. These central components biochemically intermingle in a ternary complex recently dubbed the "apoptosome." The C elegans protein EGL-1 and its mammalian counterparts, pro-apoptotic members of the bcl-2 family, induce cell death by disrupting apoptosome interactions. Thus, EGL-1 may represent a primordial signal integrator for the apoptosome. Various biochemical processes including oligomerization, adenosine triphosphate ATP/dATP binding, and cytochrome c interaction play a role in regulating the ternary death complex. Recent studies suggest that cell death receptors, such as CD95, may amplify their suicide signal by activating the apoptosome. These mutual associations by core components of the suicide apparatus provide a molecular framework in which diverse death signals likely interface. Understanding the apoptosome and its cellular connections will facilitate the design of novel therapeutic strategies for cancer and other disease states in which apoptosis plays a pivotal role.
Topics: Adenosine Triphosphate; Animals; Apoptosis; Caenorhabditis elegans Proteins; Calcium-Binding Proteins; Caspase 8; Caspase 9; Caspases; Cysteine Endopeptidases; Helminth Proteins; Humans; Repressor Proteins
PubMed: 10935465
DOI: 10.1038/sj.neo.7900003 -
Cellular and Molecular Life Sciences :... Feb 2015Programmed cell death plays a central role in the regulation of homeostasis and development of multicellular organisms. Deregulation of programmed cell death is... (Review)
Review
Programmed cell death plays a central role in the regulation of homeostasis and development of multicellular organisms. Deregulation of programmed cell death is connected to a number of disorders, including cancer and autoimmune diseases. Initiation of cell death occurs in the multiprotein complexes or high molecular weight platforms. Composition, structure, and molecular interactions within these platforms influence the cellular decision toward life or death and, therefore, define the induction of a particular cell death program. Here, we discuss in detail the key cell-death complexes-including DISC, complex II, and TNFRI complex I/II, and the necrosome, RIPoptosome, apoptosome, and PIDDosome-that control apoptosis or necroptosis pathways as well as their regulation. The possibility of their pharmacological targeting leading to the development of new strategies of interference with cell death programs via control of the high molecular weight platforms will be discussed.
Topics: Apoptosomes; Caspase 2; Cell Death; Death Domain Receptor Signaling Adaptor Proteins; Models, Biological; Multiprotein Complexes; Necrosis; Signal Transduction
PubMed: 25323133
DOI: 10.1007/s00018-014-1757-2 -
International Journal of Molecular... 2012Apoptosis, also called programmed cell death, is an orderly cellular suicide program that is critical for the development, immune regulation and homeostasis of a... (Review)
Review
Apoptosis, also called programmed cell death, is an orderly cellular suicide program that is critical for the development, immune regulation and homeostasis of a multi-cellular organism. Failure to control this process can lead to serious human diseases, including many types of cancer, neurodegenerative diseases, and autoimmununity. The process of apoptosis is mediated by the sequential activation of caspases, which are cysteine proteases. Initiator caspases, such as caspase-2, -8, -9, and -10, are activated by formation of caspase-activating complexes, which function as a platform to recruit caspases, providing proximity for self-activation. Well-known initiator caspase-activating complexes include (1) DISC (Death Inducing Signaling Complex), which activates caspases-8 and 10; (2) Apoptosome, which activates caspase-9; and (3) PIDDosome, which activates caspase-2. Because of the fundamental biological importance of capases, many structural and biochemical studies to understand the molecular basis of assembly mechanism of caspase-activating complexes have been performed. In this review, we summarize previous studies that have examined the structural and biochemical features of caspase-activating complexes. By analyzing the structural basis for the assembly mechanism of the caspase-activating complex, we hope to provide a comprehensive understanding of caspase activation by these important oligomeric complexes.
Topics: Apoptosis; Apoptosomes; Caspases; Death Domain Receptor Signaling Adaptor Proteins; Enzyme Activation; Humans; Multienzyme Complexes; Protein Structure, Tertiary; Signal Transduction
PubMed: 22606010
DOI: 10.3390/ijms13044807