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Cancer Letters Jan 2010The isoprenoid alcohol farnesol is an effective inducer of cell cycle arrest and apoptosis in a variety of carcinoma cell types. In addition, farnesol has been reported... (Review)
Review
The isoprenoid alcohol farnesol is an effective inducer of cell cycle arrest and apoptosis in a variety of carcinoma cell types. In addition, farnesol has been reported to inhibit tumorigenesis in several animal models suggesting that it functions as a chemopreventative and anti-tumor agent in vivo. A number of different biochemical and cellular processes have been implicated in the growth-inhibitory and apoptosis-inducing effects of farnesol. These include regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and CTP:phosphocholine cytidylyltransferase alpha (CCTalpha), rate-limiting enzymes in the mevalonate pathway and phosphatidylcholine biosynthesis, respectively, and the generation of reactive oxygen species. In some cell types the action of farnesol is mediated through nuclear receptors, including activation of farnesoid X receptor (FXR) and peroxisome proliferator-activated receptors (PPARs). Recent studies have revealed that induction of endoplasmic reticulum (ER) stress and the subsequent activation of the unfolded protein response (UPR) play a critical role in the induction of apoptosis by farnesol in lung carcinoma cells. This induction was found to be dependent on the activation of the MEK1/2-ERK1/2 pathway. In addition, farnesol induces activation of the NF-kappaB signaling pathway and a number of NF-kappaB target genes. Optimal activation of NF-kappaB was reported to depend on the phosphorylation of p65/RelA by the MEK1/2-MSK1 signaling pathway. In a number of cells farnesol-induced apoptosis was found to be linked to activation of the apoptosome. This review provides an overview of the biochemical and cellular processes regulated by farnesol in relationship to its growth-inhibitory, apoptosis-promoting, and anti-tumor effects.
Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosomes; Cell Proliferation; Cytidine Diphosphate Choline; Endoplasmic Reticulum; Farnesol; Humans; Hydroxymethylglutaryl CoA Reductases; Mitogen-Activated Protein Kinases; NF-kappa B; Neoplasms; Oxidative Stress; PPAR gamma; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Thyroid Hormone Receptors beta; Unfolded Protein Response
PubMed: 19520495
DOI: 10.1016/j.canlet.2009.05.015 -
Journal of Cellular and Molecular... Jun 2009The mitochondrial pathway to apoptosis is a major pathway of physiological cell death in vertebrates. The mitochondrial cell death pathway commences when apoptogenic... (Review)
Review
The mitochondrial pathway to apoptosis is a major pathway of physiological cell death in vertebrates. The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP). BCL-2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro-apoptotic B cell lymphoma (BCL)-2 proteins, BCL-2 associated x protein and BCL-2 antagonist killer 1 induce MOMP whereas the anti-apoptotic BCL-2 proteins, BCL-2, BCL-x(l) and myeloid cell leukaemia 1 prevent MOMP from occurring. The release of pro-apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades. These pathways are important for normal cellular homeostasis and play key roles in the pathogenesis of many diseases. In this review, we will provide a brief overview of the mitochondrial death pathway and focus on a selection of diseases whose pathogenesis involves the mitochondrial death pathway and we will examine the various pharmacological approaches that target this pathway.
Topics: Animals; Apoptosis; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Models, Biological; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; bcl-2-Associated X Protein
PubMed: 19220575
DOI: 10.1111/j.1582-4934.2009.00697.x -
PloS One 2016The release of cytochrome c from the inner mitochondrial membrane, where it is anchored by caridolipin, triggers the formation of the Apaf-1 apoptosome. Cardiolipin also...
The release of cytochrome c from the inner mitochondrial membrane, where it is anchored by caridolipin, triggers the formation of the Apaf-1 apoptosome. Cardiolipin also interacts with NLRP3 recruiting NLRP3 to mitochondria and facilitating inflammasome assembly. In this study we investigated whether cytosolic cytochrome c impacts NLRP3 inflammasome activation in macrophages. We report that cytochrome c binds to the LRR domain of NLRP3 and that cytochrome c reduces the interactions between NLRP3 and cardiolipin and between NLRP3 and NEK7, a recently recognized component of the NLRP3 inflammasome needed for NLRP3 oligomerization. Protein transduction of cytochrome c impairs NLRP3 inflammasome activation, while partially silencing cytochrome c expression enhances it. The addition of cytochrome c to an in vitro inflammasome assay severely limited caspase-1 activation. We propose that there is a crosstalk between the NLRP3 inflammasome and apoptosome pathways mediated by cytochrome c, whose release during apoptosis acts to limit NLRP3 inflammasome activation.
Topics: Apoptosis; Cardiolipins; Cytochromes c; Cytosol; HEK293 Cells; Humans; Inflammasomes; NIMA-Related Kinases; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 28030552
DOI: 10.1371/journal.pone.0167636 -
Current Opinion in Cell Biology Dec 2010Multi-cellular animals have evolved a variety of mechanisms to respond to diverse apoptotic stimuli. In general these proceed through activation of apical caspases and... (Review)
Review
Multi-cellular animals have evolved a variety of mechanisms to respond to diverse apoptotic stimuli. In general these proceed through activation of apical caspases and culminate in executioner caspase activation and cell death. Because of the breadth of possible initiators, various molecular platforms are used to trigger different apical caspases. Although some common protein domains are used to assemble the apoptosome, the PIDDosome and death receptor complexes, an array of checks-and-balances are employed to ensure appropriate activation. Notwithstanding, these pathways share the underlying principle of proximity-dependent activation and post-translational modification. Here we will describe our current structural understanding of assembly and regulation of these signaling platforms.
Topics: Animals; Apoptosomes; Caspases; Cell Death; Enzyme Activation; Models, Molecular; Protein Structure, Tertiary; Signal Transduction; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
PubMed: 20817427
DOI: 10.1016/j.ceb.2010.08.004 -
ELife Oct 2016In response to cell death signals, an active apoptosome is assembled from Apaf-1 and procaspase-9 (pc-9). Here we report a near atomic structure of the active human...
In response to cell death signals, an active apoptosome is assembled from Apaf-1 and procaspase-9 (pc-9). Here we report a near atomic structure of the active human apoptosome determined by cryo-electron microscopy. The resulting model gives insights into cytochrome c binding, nucleotide exchange and conformational changes that drive assembly. During activation an acentric disk is formed on the central hub of the apoptosome. This disk contains four Apaf-1/pc-9 CARD pairs arranged in a shallow spiral with the fourth pc-9 CARD at lower occupancy. On average, Apaf-1 CARDs recruit 3 to 5 pc-9 molecules to the apoptosome and one catalytic domain may be parked on the hub, when an odd number of zymogens are bound. This suggests a stoichiometry of one or at most, two pc-9 dimers per active apoptosome. Thus, our structure provides a molecular framework to understand the role of the apoptosome in programmed cell death and disease.
Topics: Apoptosomes; Apoptotic Protease-Activating Factor 1; Caspase 9; Cryoelectron Microscopy; Humans
PubMed: 27697150
DOI: 10.7554/eLife.17755 -
Postepy Higieny I Medycyny... Feb 2013Apoptosis, also called programmed cell death, is a physiological process that causes a number of morphological and biochemical changes, occurring in the cell and leading... (Review)
Review
Apoptosis, also called programmed cell death, is a physiological process that causes a number of morphological and biochemical changes, occurring in the cell and leading to its death. Along with the processes of proliferation, differentiation and maturation, it is responsible for controlling the amount and types of cells, removing those that are unnecessary or dangerous for the organism. The most important enzymes involved in apoptosis are caspases, which hydrolyze the structural and functional proteins, ultimately leading to cell death. The caspases are synthesized in the cell as inactive zymogens and have to be activated in order to perform their functions. Two pathways lead to the activation of caspases: the extrinsic pathway associated with membrane receptors and their ligands, and the intrinsic pathway dependent on mitochondria. The central element in the mitochondrial pathway is a special protein complex, the apoptosome, which enables and facilitates the activation of procaspase 9. Apaf-1, cytochrome c and dATP/ATP are needed to form the apoptosome. Active apoptosomes arise only in response to apoptotic agents. There are many factors regulating apoptosome formation in physiological conditions. It was shown that disorders in apoptosome formation have great importance in the pathogenesis of cancer and the occurrence of resistance to chemotherapy. Therefore, research continues on finding compounds which are able to induce or inhibit the formation of the apoptosome. The results of this research will have great importance for the treatment of cancers or diseases resulting from an excessively prolonged process of apoptosis. In this paper the general characteristics of the apoptosome, its role and mechanism of formation are presented. Additional information is given on the regulation of its activity and on the role of disturbance of apoptosome activity in cancerogenesis and chemoresistance. Particular attention is paid to those compounds that are able to influence the formation and activation of the apoptosome, and may in future be interesting therapeutic tools.
Topics: Apoptosis; Apoptosomes; Apoptotic Protease-Activating Factor 1; Caspase 9; Cytochromes c; Enzyme Activation; Humans; Hydrolysis; Ligands; Mitochondria; Neoplasms
PubMed: 23475483
DOI: 10.5604/17322693.1032333 -
The EMBO Journal Mar 2001During apoptosis, release of cytochrome c initiates dATP-dependent oligomerization of Apaf-1 and formation of the apoptosome. In a cell-free system, we have addressed...
During apoptosis, release of cytochrome c initiates dATP-dependent oligomerization of Apaf-1 and formation of the apoptosome. In a cell-free system, we have addressed the order in which apical and effector caspases, caspases-9 and -3, respectively, are recruited to, activated and retained within the apoptosome. We propose a multi-step process, whereby catalytically active processed or unprocessed caspase-9 initially binds the Apaf-1 apoptosome in cytochrome c/dATP-activated lysates and consequently recruits caspase-3 via an interaction between the active site cysteine (C287) in caspase-9 and a critical aspartate (D175) in caspase-3. We demonstrate that XIAP, an inhibitor-of-apoptosis protein, is normally present in high molecular weight complexes in unactivated cell lysates, but directly interacts with the apoptosome in cytochrome c/dATP-activated lysates. XIAP associates with oligomerized Apaf-1 and/or processed caspase-9 and influences the activation of caspase-3, but also binds activated caspase-3 produced within the apoptosome and sequesters it within the complex. Thus, XIAP may regulate cell death by inhibiting the activation of caspase-3 within the apoptosome and by preventing release of active caspase-3 from the complex.
Topics: Apoptosis; Apoptotic Protease-Activating Factor 1; Aspartic Acid; Caspase 3; Caspase 9; Caspases; Cell Line; Deoxyadenine Nucleotides; Enzyme Activation; Humans; Macromolecular Substances; Models, Biological; Precipitin Tests; Protein Binding; Protein Processing, Post-Translational; Proteins; Recombinant Proteins; X-Linked Inhibitor of Apoptosis Protein
PubMed: 11230124
DOI: 10.1093/emboj/20.5.998 -
Biochimica Et Biophysica Acta Apr 2011The assembling of distinct signaling protein complexes at the endoplasmic reticulum (ER) membrane controls several stress responses related to calcium homeostasis,... (Review)
Review
The assembling of distinct signaling protein complexes at the endoplasmic reticulum (ER) membrane controls several stress responses related to calcium homeostasis, autophagy, ER morphogenesis and protein folding. Diverse pathological conditions interfere with the function of the ER altering protein folding, a condition known as "ER stress". Adaptation to ER stress depends on the activation of the unfolded protein response (UPR) and protein degradation pathways such as autophagy. Under chronic or irreversible ER stress, cells undergo apoptosis, where the BCL-2 protein family plays a crucial role at the mitochondria to trigger cytochrome c release and apoptosome assembly. Several BCL2 family members also regulate physiological processes at the ER through dynamic interactomes. Here we provide a comprehensive view of the roles of the BCL-2 family of proteins in mediating the molecular crosstalk between the ER and mitochondria to initiate apoptosis, in addition to their emerging functions in adaptation to stress, including autophagy, UPR, calcium homeostasis and organelle morphogenesis. We envision a model where BCL-2-containing complexes may operate as stress rheostats that, beyond their known apoptosis functions at the mitochondria, determine the amplitude and kinetics of adaptive responses against ER-related injuries. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.
Topics: Animals; Apoptosis; Endoplasmic Reticulum; Humans; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Stress, Physiological
PubMed: 21122809
DOI: 10.1016/j.bbamcr.2010.11.012 -
Structure (London, England : 1993) Aug 2011Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway. We now provide further evidence that caspase recruitment domains of...
Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway. We now provide further evidence that caspase recruitment domains of pc-9 and Apaf-1 form a CARD-CARD disk that is flexibly tethered to the apoptosome. In addition, a 3D reconstruction of the pc-9 apoptosome was calculated without symmetry restraints. In this structure, p20 and p10 catalytic domains of a single pc-9 interact with nucleotide binding domains of adjacent Apaf-1 subunits. Together, disk assembly and pc-9 binding create an asymmetric proteolysis machine. We also show that CARD-p20 and p20-p10 linkers play important roles in pc-9 activation. Based on the data, we propose a proximity-induced association model for pc-9 activation on the apoptosome. We also show that pc-9 and caspase-3 have overlapping binding sites on the central hub. These binding sites may play a role in pc-3 activation and could allow the formation of hybrid apoptosomes with pc-9 and caspase-3 proteolytic activities.
Topics: Amino Acid Sequence; Apoptosis; Apoptosomes; Apoptotic Protease-Activating Factor 1; CARD Signaling Adaptor Proteins; Caspase 3; Caspase 9; Enzyme Activation; Humans; Models, Molecular; Molecular Sequence Data; Mutation, Missense; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Quaternary; Thrombin
PubMed: 21827945
DOI: 10.1016/j.str.2011.07.001 -
Mitochondrion May 2014Cancer cells are resistant to conventional chemotherapy and radiotherapy, however, the molecular mechanisms of resistance to therapy remain unclear. Cellular survival... (Review)
Review
Cancer cells are resistant to conventional chemotherapy and radiotherapy, however, the molecular mechanisms of resistance to therapy remain unclear. Cellular survival machinery protects mitochondrial integrity against endogenous or exogenous stresses. Prodeath molecules orchestrate around mitochondria to initiate and execute cell death in cancer, and also play an underappreciated role in survival of cancer cells. Prosurvival mechanisms can operate at mitochondrial and postmitochondrial levels to attenuate core apoptotic death program. It is intriguing to explore how prosurvival and prodeath molecules crosstalk to regulate mitochondrial functions leading to increased cancer cell survival. This review describes some putative survival mechanisms at mitochondria, which may play a role in designing effective agents for cancer prevention and therapy. These survival pathways may also have significance in understanding other human pathophysiological conditions including diabetes, cardiovascular, autoimmune, and neurodegenerative diseases.
Topics: Cell Survival; Humans; Metabolic Networks and Pathways; Mitochondria; Neoplasms; Signal Transduction
PubMed: 24333692
DOI: 10.1016/j.mito.2013.11.005