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Showing papers on "Apoptosis published in 2003"


Journal ArticleDOI
TL;DR: Evidence that p53 translocation to the mitochondria occurs in vivo in irradiated thymocytes is provided and it is shown that the p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BclXL and Bcl2 proteins, resulting in cytochrome c release.

1,751 citations


Journal ArticleDOI
16 May 2003-Science
TL;DR: Microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range, indicating that endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth.
Abstract: About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.

1,487 citations


Journal ArticleDOI
TL;DR: Recent progress in understanding the biochemical mechanisms and regulation of the caspase activation pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values are focused on.
Abstract: Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death. In this review, we focus on the recent progress in understanding the biochemical mechanisms and regulation of the pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values.

1,303 citations


Journal ArticleDOI
TL;DR: In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days.
Abstract: 1. However, its potential to treat or prevent disease remains unproven. Fas-mediated apoptosis is implicated in a broad spectrum of liver diseases, where inhibiting hepatocyte death is life-saving 2 . We investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the gene Fas (also known as Tnfrsf6), encoding the Fas receptor, to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from mice treated with Fas siRNA were resistant to apoptosis when exposed to Fas-specific antibody or co-cultured with concanavalin A (ConA)-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before ConA challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. Administering Fas siRNA beginning one week after initiating weekly ConA injections protected mice from liver fibrosis. In a more fulminant hepatitis induced by injecting agonistic Fasspecific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days. Silencing Fas expression with RNAi holds therapeutic promise to prevent liver injury by protecting hepatocytes from cytotoxicity.

1,176 citations


Journal ArticleDOI
TL;DR: A multitude of mechanisms are employed by p53 to ensure efficient induction of apoptosis in a stage-, tissue- and stress-signal-specific manner, and constitutes an attractive target for cancer therapy.
Abstract: Exposure to cellular stress can trigger the p53 tumor suppressor, a sequence-specific transcription factor, to induce cell growth arrest or apoptosis. The choice between these cellular responses is influenced by many factors, including the type of cell and stress, and the action of p53 co-activators. p53 stimulates a wide network of signals that act through two major apoptotic pathways. The extrinsic, death receptor pathway triggers the activation of a caspase cascade, and the intrinsic, mitochondrial pathway shifts the balance in the Bcl-2 family towards the pro-apoptotic members, promoting the formation of the apoptosome, and consequently caspase-mediated apoptosis. The impact of these two apoptotic pathways may be enhanced when they converge through Bid, which is a p53 target. The majority of these apoptotic effects are mediated through the induction of specific apoptotic target genes. However, p53 can also promote apoptosis by a transcription-independent mechanism under certain conditions. Thus, a multitude of mechanisms are employed by p53 to ensure efficient induction of apoptosis in a stage-, tissue- and stress-signal-specific manner. Manipulation of the apoptotic functions of p53 constitutes an attractive target for cancer therapy.

1,128 citations


Journal ArticleDOI
24 Nov 2003-Oncogene
TL;DR: A large number of caspases from the cysteine proteases family play important roles in regulating apoptosis, and the mechanisms by which they mediate apoptosis and a variety of physiological and pathological processes are studied.
Abstract: Caspases are a family of cysteine proteases that play important roles in regulating apoptosis. A decade of research has generated a wealth of information on the signal transduction pathways mediated by caspases, the distinct functions of individual caspases and the mechanisms by which caspases mediate apoptosis and a variety of physiological and pathological processes.

1,127 citations


Journal ArticleDOI
TL;DR: A number of proteins have been reported to regulate formation or activity of the DISC, the complex of proteins that forms upon triggering of CD95 that is essential for induction of apoptosis.
Abstract: CD95 (APO-1/Fas) is a prototype death receptor characterized by the presence of an 80 amino acid death domain in its cytoplasmic tail. This domain is essential for the recruitment of a number of signaling components upon activation by either agonistic anti-CD95 antibodies or cognate CD95 ligand that initiate apoptosis. The complex of proteins that forms upon triggering of CD95 is called the death-inducting signaling complex (DISC). The DISC consists of an adaptor protein and initiator caspases and is essential for induction of apoptosis. A number of proteins have been reported to regulate formation or activity of the DISC. This review discusses recent developments in this area of death receptor research.

1,096 citations


Journal ArticleDOI
TL;DR: Observations provide direct evidence that endogenous SIRT1 protein regulates p53 acetylation and p53-dependent apoptosis, and show that the function of this enzyme is required for specific developmental processes.
Abstract: SIRT1 is a mammalian homolog of the Saccharomyces cerevisiae chromatin silencing factor Sir2 Dominant-negative and overexpression studies have implicated a role for SIRT1 in deacetylating the p53 tumor suppressor protein to dampen apoptotic and cellular senescence pathways To elucidate SIRT1 function in normal cells, we used gene-targeted mutation to generate mice that express either a mutant SIRT1 protein that lacks part of the catalytic domain or has no detectable SIRT1 protein at all Both types of SIRT1 mutant mice and cells had essentially the same phenotypes SIRT1 mutant mice were small, and exhibited notable developmental defects of the retina and heart, and only infrequently survived postnatally Moreover, SIRT1-deficient cells exhibited p53 hyperacetylation after DNA damage and increased ionizing radiation-induced thymocyte apoptosis In SIRT1-deficient embryonic fibroblasts, however, p53 hyperacetylation after DNA damage was not accompanied by increased p21 protein induction or DNA damage sensitivity Together, our observations provide direct evidence that endogenous SIRT1 protein regulates p53 acetylation and p53-dependent apoptosis, and show that the function of this enzyme is required for specific developmental processes

1,067 citations


Journal ArticleDOI
TL;DR: The identification of the Drosophila miRNA mir-14 as a cell death suppressor is reported, and possible relationships between these phenotypes are discussed.

1,039 citations


Journal ArticleDOI
TL;DR: The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances, and oversuppression of these pathways may also lead to increased viral susceptibility and/or decreased tumor cell killing.
Abstract: Virtually all of the measurable cell-mediated cytotoxicity delivered by cytotoxic T lymphocytes and natural killer cells comes from either the granule exocytosis pathway or the Fas pathway. The granule exocytosis pathway utilizes perforin to traffic the granzymes to appropriate locations in target cells, where they cleave critical substrates that initiate DNA fragmentation and apoptosis; granzymes A and B induce death via alternate, nonoverlapping pathways. The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances. The interplay between these two cytotoxic systems provides opportunities for therapeutic interventions to control autoimmune diseases and graft vs. host disease, but oversuppression of these pathways may also lead to increased viral susceptibility and/or decreased tumor cell killing.

1,018 citations


Journal ArticleDOI
TL;DR: A unified caspase activation hypothesis is proposed whereby apical caspases are activated by dimerization of monomeric zymogens, and single amino acid substitutions at the dimer interface abrogate the activity of caspased-8 and -9 introduced into recipient mammalian cells.

Journal ArticleDOI
TL;DR: Hepatocyte apoptosis is significantly increased in patients with NASH and correlates with disease severity, suggesting that antiapoptotic therapy may be useful in this syndrome.

Journal ArticleDOI
TL;DR: It is proposed that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterol-induced apoptosis in macrophages.
Abstract: Excess cellular cholesterol induces apoptosis in macrophages, an event likely to promote progression of atherosclerosis. The cellular mechanism of cholesterol-induced apoptosis is unknown but had previously been thought to involve the plasma membrane. Here we report that the unfolded protein response (UPR) in the endoplasmic reticulum is activated in cholesterolloaded macrophages, resulting in expression of the cell death effector CHOP. Cholesterol loading depletes endoplasmic reticulum calcium stores, an event known to induce the UPR. Furthermore, endoplasmic reticulum calcium depletion, the UPR, caspase-3 activation and apoptosis are markedly inhibited by selective inhibition of cholesterol trafficking to the endoplasmic reticulum, and Chop −/− macrophages are protected from cholesterol-induced apoptosis. We propose that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterolinduced apoptosis in macrophages.

Journal ArticleDOI
TL;DR: Pharmacologic interference with the induction or completion of apoptosis holds promise for the treatment of neurodegenerative diseases, and clinical trials with one such agent are already under way.
Abstract: A form of cell death called apoptosis is a prominent feature in a broad spectrum of neurodegenerative diseases, ranging from stroke to Huntington's disease. Hypoxia, toxic cytokines, damage to mitochondria, and noxious peptides are capable of inducing apoptosis; each of these mechanisms can account for the death of specific types of neurons in neurodegenerative diseases. Pharmacologic interference with the induction or completion of apoptosis holds promise for the treatment of these disorders, and clinical trials with one such agent are already under way.

Journal ArticleDOI
24 Nov 2003-Oncogene
TL;DR: Recent insights into the apoptosis-signaling pathways stimulated by TRAIL are summarized, and the current understanding of the physiological role of this ligand and the potential of its application for cancer therapy and prevention are presented.
Abstract: Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family of ligands capable of initiating apoptosis through engagement of its death receptors. TRAIL selectively induces apoptosis of a variety of tumor cells and transformed cells, but not most normal cells, and therefore has garnered intense interest as a promising agent for cancer therapy. TRAIL is expressed on different cells of the immune system and plays a role in both T-cell- and natural killer cell-mediated tumor surveillance and suppression of suppressing tumor metastasis. Some mismatch-repair-deficient tumors evade TRAIL-induced apoptosis and acquire TRAIL resistance through different mechanisms. Death receptors, members of the TNF receptor family, signal apoptosis independently of the p53 tumor-suppressor gene. TRAIL treatment in combination with chemo- or radiotherapy enhances TRAIL sensitivity or reverses TRAIL resistance by regulating the downstream effectors. Efforts to identify agents that activate death receptors or block specific effectors may improve therapeutic design. In this review, we summarize recent insights into the apoptosis-signaling pathways stimulated by TRAIL, present our current understanding of the physiological role of this ligand and the potential of its application for cancer therapy and prevention.

Journal ArticleDOI
TL;DR: The MPT is a common pathway leading to both nec rotic and apoptotic cell death after ischemia/reperfusion, and the balance between ATP depletion after the MPT and ATP generation by glycolysis determines whether the fate of cells will be apoptotic or necrotic death.

Journal ArticleDOI
24 Nov 2003-Oncogene
TL;DR: The potential underlying mechanisms involved in the regulation of the mitochondrial checkpoint are reviewed and pathways for ER–mitochondrial crosstalk pertinent to a number of cell death stimuli are discussed.
Abstract: Apoptotic programmed cell death pathways are activated by a diverse array of cell extrinsic and intrinsic signals, most of which are ultimately coupled to the activation of effector caspases. In many instances, this involves an obligate propagation through mitochondria, causing egress of critical proapoptotic regulators to the cytosol. Central to the regulation of the mitochondrial checkpoint is a complex three-way interplay between members of the BCL-2 family, which are comprised of an antiapoptotic subgroup including BCL-2 itself, and the proapoptotic BAX,BAK and BH3-domain-only subgroups. Constituents of all three of these BCL-2 classes, however, also converge on the endoplasmic reticulum (ER), an organelle whose critical contributions to apoptosis is only now becoming apparent. In addition to propagating death-inducing stress signals itself, the ER also contributes in a fundamental way to Fas-mediated apoptosis and to p53-dependent pathways resulting from DNA damage and oncogene expression. Mobilization of ER calcium stores can initiate the activation of cytoplasmic death pathways as well as sensitize mitochondria to direct proapoptotic stimuli. Additionally, the existence of BCL-2-regulated initiator procaspase activation complexes at the ER membrane has also been described. Here, we review the potential underlying mechanisms involved in these events and discuss pathways for ER-mitochondrial crosstalk pertinent to a number of cell death stimuli.

Journal ArticleDOI
15 Mar 2003-Blood
TL;DR: This study found that subtoxic concentrations of PS-341 potently sensitized MM cell lines and patient cells to DNA-damaging chemotherapeutic agents such as doxorubicin and melphalan, including cells resistant to these drugs and those isolated from a patient who had relapsed afterPS-341 monotherapy.

Journal ArticleDOI
TL;DR: It is demonstrated that monomeric caspase-9 is catalytically inactive due to the absence of a supporting sequence element that could be provided by homodimerization, which defines a unified mechanism for the activation of all caspases.

Journal ArticleDOI
TL;DR: Necrosis appears to be a specific form of execution phase of programmed cell death, and there are several examples of necrosis during embryogenesis, a normal tissue renewal, and immune response.

Journal ArticleDOI
01 Feb 2003-Blood
TL;DR: It is found that curcumin down-regulates NF-κB in human MM cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of MM patients with this pharmacologically safe agent.

Journal ArticleDOI
23 Apr 2003-JAMA
TL;DR: In this paper, the authors examined the hypothesis that an injurious ventilatory strategy may lead to end-organ epithelial cell apoptosis and organ dysfunction, and showed that a lung protection strategy led to increased rates of epithelialcell apoptosis in the kidney.
Abstract: ContextRecent clinical trials have demonstrated a decrease in multiple organ dysfunction syndrome (MODS) and mortality in patients with acute respiratory distress syndrome (ARDS) treated with a protective ventilatory strategy.ObjectiveTo examine the hypothesis that an injurious ventilatory strategy may lead to end-organ epithelial cell apoptosis and organ dysfunction.Design and SettingIn vivo animals: 24 rabbits with acid-aspiration lung injury were ventilated with injurious or noninjurious ventilatory strategies. In vitro: rabbit epithelial cells were exposed to plasma from in vivo rabbit studies. In vivo human: plasma samples from patients included in a previous randomized controlled trial examining a lung protective strategy were analyzed (lung protection group, n = 9 and controls, n = 11).Main Outcome MeasuresIn vivo animals: biochemical markers of liver and renal dysfunction; apoptosis in end organs. In vitro: induction of apoptosis in LLC-RK1 renal tubular epithelial cells. In vivo human: correlation of plasma creatinine and soluble Fas ligand.ResultsThe injurious ventilatory strategy led to increased rates of epithelial cell apoptosis in the kidney (mean [SE]: injurious, 10.9% [0.88%]; noninjurious, 1.86% [0.17%]; P<.001) and small intestine villi (injurious, 6.7% [0.66%]; noninjurious, 0.97% [0.14%]; P<.001), and led to the elevation of biochemical markers indicating renal dysfunction in vivo. Induction of apoptosis was increased in LLC-RK1 cells incubated with plasma from rabbits ventilated with injurious ventilatory strategy at 4 hours (P = .03) and 8 hours (P = .002). The Fas:Ig, a fusion protein that blocks soluble Fas ligand, attenuated induction of apoptosis in vitro. There was a significant correlation between changes in soluble Fas ligand and changes in creatinine in patients with ARDS (R = 0.64, P = .002).ConclusionsMechanical ventilation can lead to epithelial cell apoptosis in the kidney and small intestine, accompanied by biochemical evidence of organ dysfunction. This may partially explain the high rate of MODS observed in patients with ARDS and the decrease in morbidity and mortality in patients treated with a lung protective strategy.

Journal ArticleDOI
TL;DR: Evidence is provided that GLP-1 added to freshly isolated human islets preserves morphology and function and inhibits cell apoptosis, and better-preserved three-dimensional islet morphology in the GLp-1-treated islets, compared with controls.
Abstract: The peptide hormone, glucagon-like peptide 1 (GLP-1), has been shown to increase glucose-dependent insulin secretion, enhance insulin gene transcription, expand islet cell mass, and inhibit -cell apoptosis in animal models of diabetes. The aim of the present study was to evaluate whether GLP-1 could improve function and inhibit apoptosis in freshly isolated human islets. Human islets were cultured fo r5di n thepresence, or absence, of GLP-1 (10 nM, added every 12 h) and studied for viability and expression of proapoptotic (caspase-3) and antiapoptotic factors (bcl-2) as well as glucose-dependent insulin production. We observed better-preserved three-dimensional islet morphology in the GLP-1-treated islets, compared with controls. Nuclear condensation, a feature of cell apoptosis, was inhibited by GLP-1. The reduction in the number of apoptotic cells in GLP-1-treated islets was particularly evident at d 3 (6.1% apoptotic nuclei in treated cultures vs. 15.5% in controls; P < 0.01) and at d 5 (8.9 vs. 18.9%; P < 0.01). The antiapoptotic effect of GLP-1 was associated with the downregulation of active caspase-3 (P < 0.001) and the up-regulation of bcl-2 (P < 0.01). The effect of GLP-1 on the intracellular levels of bcl-2 and caspase-3 was observed at the mRNA and protein levels. Intracellular insulin content was markedly enhanced in islets cultured with GLP-1 vs. control (P < 0.001, at d 5), and there was a parallel GLP-1-dependent potentiation of glucose-dependent insulin secretion (P < 0.01 at d 3; P < 0.05 at d 5). Our findings provide evidence that GLP-1 added to freshly isolated human islets preserves morphology and function and inhibits cell apoptosis. (Endocrinology 144: 5149 –5158, 2003)

Journal Article
TL;DR: This work has identified the first low molecular weight compound, designated FK866, which induces apoptosis by highly specific, noncompetitive inhibition of nicotinamide phosphoribosyltransferase (NAPRT), a key enzyme in the regulation of NAD+ biosynthesis from the natural precursor Nicotinamide.
Abstract: Deregulation of apoptosis, the physiological form of cell death, is closely associated with immunological diseases and cancer. Apoptosis is activated either by death receptor-driven or mitochondrial pathways, both of which may provide potential targets for novel anticancer drugs. Although several ligands stimulating death receptors have been described, the actual molecular events triggering the mitochondrial pathway are largely unknown. Here, we show initiation of apoptosis by gradual depletion of the intracellular coenzyme NAD+. We identified the first low molecular weight compound, designated FK866, which induces apoptosis by highly specific, noncompetitive inhibition of nicotinamide phosphoribosyltransferase (NAPRT), a key enzyme in the regulation of NAD+ biosynthesis from the natural precursor nicotinamide. Interference with this enzyme does not primarily intoxicate cells because the mitochondrial respiratory activity and the NAD+ -dependent redox reactions involved remain unaffected as long as NAD+ is not effectively depleted by catabolic reactions. Certain tissues, however, have a high turnover of NAD+ through its cleavage by enzymes like poly(ADP-ribose) polymerase. Such cells often rely on the more readily available nicotinamide pathway for NAD+ synthesis and undergo apoptosis after inhibition of NAPRT, whereas cells effectively using the nicotinic acid pathway for NAD+ synthesis remain unaffected. In support of this concept, FK866 effectively induced delayed cell death by apoptosis in HepG2 human liver carcinoma cells with an IC(50) of approximately 1 nM, did not directly inhibit mitochondrial respiratory activity, but caused gradual NAD+ depletion through specific inhibition of NAPRT. This enzyme, when partially purified from K562 human leukemia cells, was noncompetitively inhibited by FK866, and the inhibitor constants were calculated to be 0.4 nM for the enzyme/substrate complex (K(i)) and 0.3 nM for the free enzyme (K(i)'), respectively. Nicotinic acid and nicotinamide were both found to have antidote potential for the cellular effects of FK866. FK866 may be used for treatment of diseases implicating deregulated apoptosis such as cancer for immunosuppression or as a sensitizer for genotoxic agents. Furthermore, it may provide an important tool for investigation of the molecular triggers of the mitochondrial pathway leading to apoptosis through enabling temporal separation of NAD+ decrease from ATP breakdown and apoptosis by several days.

Journal ArticleDOI
TL;DR: Biochemical analysis of an apoptotic response triggered by UV irradiation of HeLa cells revealed that the elimination of cytosolic inhibitors is required for mitochondrial release of cytochrome c and subsequent caspase activation.
Abstract: Ultraviolet (UV) irradiation of HeLa cells triggers an apoptotic response mediated by mitochondria. Biochemical analysis of this response revealed that the elimination of cytosolic inhibitors is required for mitochondrial release of cytochrome c and subsequent caspase activation. These inhibitors were found to be Mcl-1 and Bcl-xL, two antiapoptotic members of the Bcl-2 family. Following UV treatment, Mcl-1 protein synthesis is blocked, the existing pool of Mcl-1 protein is rapidly degraded by the proteasome, and cytosolic Bcl-xL translocates to the mitochondria. These events are sequential; the elimination of Mcl-1 is required for the translocation of Bcl-xL. The disappearance of Mcl-1 is also required for other mitochondrial apoptotic events including Bax translocation, cytochrome c release, and caspase activation.

Journal ArticleDOI
TL;DR: It is suggested that the balance between PUMA and p21 is pivotal in determining the responses to p53 activation and provide a model for understanding the basis of p53 mutations in human cancer.
Abstract: Although several genes that might mediate p53-induced apoptosis have been proposed, none have previously been shown to play an essential role in this process through a rigorous gene disruption approach. We used a gene-targeting approach to evaluate p53-mediated death in human colorectal cancer cells. Expression of p53 in these cells induces growth arrest through transcriptional activation of the cyclin-dependent kinase inhibitor p21. If p21 is disrupted via gene targeting, the cells die through apoptosis. If the PUMA gene is also disrupted in such cells, apoptosis is prevented. The effects of PUMA on apoptosis were observed after exogenous overexpression of p53 as well as after exposure to hypoxia, a physiologic activator of p53, and DNA damage. The PUMA protein interacts with Bcl-XL and promotes mitochondrial translocation and multimerization of Bax. Accordingly, genetic disruption of BAX makes cells resistant to the apoptosis resulting from PUMA expression. These results suggest that the balance between PUMA and p21 is pivotal in determining the responses to p53 activation and provide a model for understanding the basis of p53 mutations in human cancer.

Journal ArticleDOI
TL;DR: It is demonstrated that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP -1 receptor activation to preservation or enhancement of β cell mass in vivo.

Journal ArticleDOI
TL;DR: This review focuses on the apoptosis signaling pathways stimulated by Apo2L/TRAIL and summarizes what is known to date about the physiological role of this ligand and the potential for its application to cancer therapy.

Journal ArticleDOI
15 Feb 2003-Blood
TL;DR: Molecular mechanisms whereby PS-341 mediates anti-MM activity are demonstrated by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH(2)-terminal kinase (JNK), caspase-8, and caspases-3; and cleaving the DNA protein kinase catalytic subunit, ATM, andMDM2.

Journal ArticleDOI
TL;DR: It is reported that APC directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling.
Abstract: Activated protein C (APC) is a systemic anti-coagulant and anti-inflammatory factor1,2,3. It reduces organ damage in animal models of sepsis, ischemic injury and stroke1,4,5 and substantially reduces mortality in patients with severe sepsis6. It was not known whether APC acts as a direct cell survival factor or whether its neuroprotective effect5,7 is secondary to its anti-coagulant and anti-inflammatory effects1,2,3. We report that APC directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling. These mechanisms are distinct from those involving upregulation of the genes encoding the anti-apoptotic Bcl-2 homolog A1 and inhibitor of apoptosis protein-1 (IAP-1) by APC in umbilical vein endothelial cells8,9. Cytoprotection of brain endothelium by APC in vitro required endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), as did its in vivo neuroprotective activity in a stroke model of mice with a severe deficiency of EPCR10. This is consistent with work showing the direct effects of APC on cultured cells via EPCR and PAR-1 (ref. 9). Moreover, the in vivo neuroprotective effects of low-dose mouse APC seemed to be independent of its anti-coagulant activity. Thus, APC protects the brain from ischemic injury by acting directly on brain cells.