Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of this study was to examine the responsiveness of an immortalized catecholaminergic neuronal line, 2N27, to various growth factors and identify those which promote catecholaminergic expression. 2N27 is a newly established neural cell line derived from fetal rat mesencephalic tissue and, thus, contains tyrosine hydroxylase (TH), a reliable marker for catecholaminergic neurons. Using TH activity as a biochemical index, we examined the responsiveness to both recognized trophic factors (NGF, TGF-beta and basic- and acidic-FGF) as well as novel, glia-derived factors present in conditioned media from several glial sources. The glial cells included MACH, a normal cell line derived from aged mouse cerebral hemispheres NBCC, normal glia derived from newborn mouse cerebral hemispheres; and C-6 glioma cells, 2B clone, passage 72, predominately astrocytes. Cells were cultured in the presence of added factors from 0 to 3 days in vitro (DIV) and were harvested on day 4. We found that 2N27 neural cells responded differentially to growth factors. No change was observed in TH activity in response to NGF, TH activity even decreased in response to b-FGF ad TGF-beta addition to the culture medium. However, a dose dependent increase in TH activity was observed following treatment with a-FGF and the increase to a-FGF was associated to an increase in cell proliferation as compared to TH increase by cAMP associated to differentiation. However, the 2N27 cells responded with a marked increase in TH when cultured in the glial cell conditioned media. We conclude that immortal cells require a variety of microenvironmental signals to maintain their phenotype.
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PMID:Catecholaminergic expression in 2N27 immortal neural cell line is enhanced by glial-derived factors. 905 60

During inflammatory reactions in the central nervous system (CNS), resident macrophages, the microglia, are exposed to Th1 cell-derived cytokines and pro-apoptotic Fas ligand (FasL). Despite the presence of TNF-alpha and IFN-gamma, both being capable of sensitizing microglia to FasL, apoptosis of microglia is not a hallmark of inflammatory diseases of the CNS. In the present study, TGF-beta is found to counteract the effect of TNF-alpha and IFN-gamma to sensitize microglia to FasL-mediated apoptosis. Resistance to Fas-mediated apoptosis by TGF-beta does not correlate with a down-regulation of Fas expression. As a key inhibitor of Fas-mediated apoptosis, we found expression of the cellular FLICE-inhibitory protein (c-FLIP) to be induced by TGF-beta in resting as well as in activated microglia. Induction of FLIP was found to depend on a mitogen-activated protein kinase kinase (MKK)-dependent pathway as shown by the use of the specific MKK-inhibitor PD98059. The presence of FLIP strongly interfered with FasL-induced activation of caspase-8 and caspase-3 preventing subsequent cell death. The presented data provide the first evidence for a TGF-beta-mediated FLIP in macrophage-like cells and suggest a mode of action for the anti-apoptotic role of TGF-beta in the CNS.
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PMID:TGF-beta induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia. 1116 11

Previous studies have implicated a number of biochemical pathways in the etiology of bipolar disorder (BD). However, the precise abnormalities underlying this disorder remain to be established. To investigate novel factors that may be important in the pathophysiology of BD, we utilized cDNA expression arrays to examine differences in expression of up to 1200 genes known to be involved in potentially relevant biochemical processes. This investigation was undertaken in post-mortem samples of frontal cortex tissue from patients with BD and matched controls, obtained (n = 10/group) from the Stanley Foundation Neuropathology Consortium. Results include significant (greater than 35% change in signal intensity) differences between BD and controls in a number of genes (n = 24). Selected targets were analyzed by RT-PCR, which confirmed a decrease in transforming growth factor-beta1 (TGF-beta 1), and an increase in both caspase-8 precursor (casp-8) and transducer of erbB2 (Tob) expression in BD. We further observed a significant decrease of TGF-beta 1 mRNA levels in BD by RT-PCR in individual post-mortem samples. Given the neuroprotective role attributed to this inhibitory cytokine, our results suggest that the down-regulation of TGF-beta 1 may lead to various neurotoxic insults potentially involved in the etiology of certain mood disorders.
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PMID:Gene expression differences in bipolar disorder revealed by cDNA array analysis of post-mortem frontal cortex. 1172 75

In this study, we evaluated the molecular mechanisms involved in morphine-induced macrophage apoptosis. Both morphine and TGF-beta promoted P38 mitogen-activated protein kinase (MAPK) phosphorylation, and this phosphorylation was inhibited by SB 202190 as well as by SB 203580. Anti-TGF-beta Ab as well as naltrexone (an opiate receptor antagonist) inhibited morphine-induced macrophage P38 MAPK phosphorylation. Anti-TGF-beta Ab also attenuated morphine-induced p53 as well as inducible NO synthase expression; in contrast, N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase, inhibited morphine-induced P38 MAPK phosphorylation and Bax expression. Morphine also enhanced the expression of both Fas and Fas ligand (FasL), whereas anti-FasL Ab prevented morphine-induced macrophage apoptosis. Moreover, naltrexone inhibited morphine-induced FasL expression. In addition, macrophages either deficient in FasL or lacking p53 showed resistance to the effect of morphine. Inhibitors of both caspase-8 and caspase-9 partially prevented the apoptotic effect of morphine on macrophages. In addition, caspase-3 inhibitor prevented morphine-induced macrophage apoptosis. These findings suggest that morphine-induced macrophage apoptosis proceeds through opiate receptors via P38 MAPK phosphorylation. Both TGF-beta and inducible NO synthase play an important role in morphine-induced downstream signaling, which seems to activate proteins involved in both extrinsic (Fas and FasL) and intrinsic (p53 and Bax) cell death pathways.
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PMID:Role of p38 mitogen-activated protein kinase phosphorylation and Fas-Fas ligand interaction in morphine-induced macrophage apoptosis. 1193 60

To date, two major apoptotic pathways, the death receptor and the mitochondrial pathway, have been well documented in mammalian cells. However, the involvement of these two apoptotic pathways, particularly the death receptor pathway, in transforming growth factor-beta 1 (TGF-beta 1)-induced apoptosis is not well understood. Herein, we report that apoptosis of human gastric SNU-620 carcinoma cells induced by TGF-beta 1 is caused by the Fas death pathway in a Fas ligand-independent manner, and that the Fas death pathway activated by TGF-beta 1 is linked to the mitochondrial apoptotic pathway via Bid mediation. We showed that TGF-beta 1 induced the expression and activation of Fas and the subsequent caspase-8-mediated Bid cleavage. Interestingly, expression of dominant negative FADD and treatment with caspase-8 inhibitor efficiently prevented TGF-beta 1-induced apoptosis, whereas the treatment with an activating CH11 or a neutralizing ZB4 anti-Fas antibody, recombinant Fas ligand, or Fas-Fc chimera did not affect activation of Fas and the subsequent induction of apoptosis by TGF-beta 1. We further demonstrated that TGF-beta 1 also activates the mitochondrial pathway showing Bid-mediated loss of mitochondrial membrane potential and subsequent cytochrome c release associated with the activations of caspase-9 and the effector caspases. Moreover, all these apoptotic events induced by TGF-beta 1 were found to be effectively inhibited by Smad3 knockdown and also completely abrogated by Smad7 expression, suggesting the involvement of the Smad3 pathway upstream of the Fas death pathway by TGF-beta 1.
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PMID:Transforming growth factor-beta 1 induces apoptosis through Fas ligand-independent activation of the Fas death pathway in human gastric SNU-620 carcinoma cells. 1459 20

Fibroblasts play an important role in reparative and inflammatory processes by synthesizing extracellular matrix components and releasing growth factors and cytokines. Fibroblast apoptosis has been observed at the termination phase of reparative or fibrotic responses, but its regulation in this context is poorly known. We investigated the susceptibility of human dermal fibroblasts (DF) to Fas-induced apoptosis and its regulation by extracellular factors potentially involved in immune-mediated inflammation and repair. DF expressed all components of the Fas apoptotic pathway: surface Fas, Fas-associated protein with death domain, and caspase-8 proteins. However, Fas activation resulted in caspase-8 activation and apoptosis only in the presence of cycloheximide (CHX). DF constitutively expressed Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein (FLIP) that was drastically down-regulated by CHX. Exogenous growth factors, cytokines, and adherence to the extracellular matrix shifted the balance of FLIP-caspase-8 proteins and modified the susceptibility of DF to Fas- or Fas-CHX-induced apoptosis. Short-term serum deprivation, suspension culture, and pretreatment with IFN-gamma or TNF-alpha increased, whereas long-term serum-free culture and pretreatment with TGF-beta or IL-10 decreased the apoptotic susceptibility of DF. Surface Fas expression was only modified by TNF-alpha and IFN-gamma, whereas all studied factors modified FLIP-caspase-8 protein expression, consistently with their pro- or antiapoptotic effects. Antisense FLIP oligonucleotides prevented resistance to Fas-induced apoptosis in DF. FLIP-caspase-8 balance seems tightly regulated in fibroblasts by extracellular factors that determine their susceptibility to Fas- or Fas-CHX-induced apoptosis. Th1 and Th regulatory cytokines display opposite effects on fibroblast apoptosis that suggest that their pro- or antifibrotic effects involve direct effects on fibroblast survival.
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PMID:Intracellular regulation of Fas-induced apoptosis in human fibroblasts by extracellular factors and cycloheximide. 1468 67

Follicular dendritic cells (FDC) constitute the framework of germinal center (GC) in secondary lymphoid follicles, and the integrity of FDC networks is critically affected by cytokines present in the GC. We have previously shown that TNF promotes Fas-mediated apoptosis of HK cells, an established FDC-like cell line, by up-regulating Fas expression. However, in the developing GC, FDC death is not a hallmark of GC despite the presence of TNF and FasL. In this study, we report that TGF-beta inhibits Fas-mediated apoptosis of HK cells by down-regulating the expression of surface Fas and caspase-8. The inhibitory effect of TGF-beta can be observed when HK cells were simultaneously treated with TNF and TGF-beta, indicating that TGF-beta counteracts the effect of TNF in sensitizing cells to Fas-mediated apoptosis. Furthermore, the deprivation of TGF-beta by injecting neutralizing TGF-beta Abs to the SRBC-immunized mice resulted in the sporadic appearance of FDC undergoing apoptosis in the lymphoid follicles, suggesting that TGF-beta functions as a naturally occurring inhibitor that rescues FDCs which are predisposed to apoptosis. Our study documents a novel function of TGF-beta in the maintenance of FDC networks.
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PMID:TGF-beta inhibits Fas-mediated apoptosis of a follicular dendritic cell line by down-regulating the expression of Fas and caspase-8: counteracting role of TGF-beta on TNF sensitization of Fas-mediated apoptosis. 1587 13

Hepatocellular carcinoma (HCC), the major manifestation of primary liver cancer, is one of the most frequent and malignant cancers worldwide, especially in Taiwan. Estrogen receptors (ERs) have been reported to play either a proliferation- or apoptosis-enhancing role in the differentiation of cancers, including HCC. In a previous experiment, we showed that transient overexpressed estrogen receptor-alpha induced early stage HCC cell line Hep 3B cell apoptosis by increasing the hTNF-alpha gene expression in a ligand-independent manner. To further clarify if the apoptotic effect occurs in poorly differentiated HCC cell line, HA22T, and elucidate the roles of ERs and TNF-alpha, DNA fragmentation and caspase activity were measured in late stage HCC cell line, HA22T, by measuring the expression of hER-alpha and hER-beta using a Tetracycline-inducible system (Tet-on). Increased DNA fragmentation and caspase-3 activity were found in hERbeta-overexpressed HA22T cells treated with estrogen (10(-8) M) but not in hERalpha-overexpressed HA22T cells. Using RT-PCR/PCR and western blotting in HA22T cells, overexpressed hER-beta was also found to increase the expression of hTNF-alpha mRNA and induce hTNF-alpha-dependent luciferase activity in a ligand-dependent manner. Additionally, LPS treatment and hER-beta overexpression both enhance caspase-8 activities, whereas neither hER-beta nor E2 treatment affected caspase-9 activities. In addition, the overexpressed hER-beta plus E2 enhanced DNA fragmentation and caspase-8 activities were only partially reduced by anti-hTNF-alpha (0.1 ng/ml), which was possibly due to the involvement of P53 and TGF-beta. Taken together, our data indicates that overexpressed hER-beta but not hER-alpha may induce caspase-8-mediated apoptosis by increasing the hTNF-alpha gene expression in a ligand-dependent manner in poorly differentiated HA22T cells.
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PMID:Opposing action of estrogen receptors alpha and beta on tumor necrosis factor-alpha gene expression and caspase-8-mediated apoptotic effects in HA22T cells. 1663 37

We have already demonstrated that interferon alfa-2b (IFN-alpha2b) induces apoptosis in isolated hepatocytes from preneoplastic rat livers via the secretion of transforming growth factor beta(1) (TGF-beta(1)), and this process is accompanied by caspase-3 activation. The aim of this study was to further investigate the mechanism of this activation. Isolated hepatocytes from preneoplastic livers induced DNA fragmentation in response to IFN-alpha2b, which was completely blocked when anti-TGF-beta(1) was added to the culture media. IFN-alpha2b mediated radical oxygen species (ROS) production that preceded the loss of mitochondrial transmembrane potential (DeltaPsi), release of cytochrome c, and activation of caspase-3. Bax levels increased in a time-dependent fashion, and Bcl-x(L) was down-regulated in the early hours of IFN-alpha2b treatment. The delayed translocation of Bid into the mitochondria was in concordance with late caspase-8 activation. In conclusion, endogenous TGF-beta(1) secreted under IFN-alpha2b stimulus seems to induce cytochrome c release through a mechanism related to Bcl-2 family members and loss of mitochondrial DeltaPsi. Bax protein could be responsible of the release of cytochrome c during the initial hours of IFN-alpha2b-induced apoptosis via TGF-beta(1). Activated Bid by caspases could amplificate the mitochondrial events, enhancing the release of cytochrome c.
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PMID:Time-dependent onset of Interferon-alpha2b-induced apoptosis in isolated hepatocytes from preneoplastic rat livers. 1737 98

Protein pin arrays assessed interactions between alphaB crystallin and 12 regulatory proteins, including EGF, FGF-2, IGF-1, NGF-beta, TGF-beta, VEGF, insulin, beta-catenin, caspase-3, caspase-8, Bcl-2, and Bcl-xL, which are important in cellular differentiation, proliferation, signaling, cytoskeletal assembly, and apoptosis. FGF-2, NGF-beta, VEGF, insulin, and beta-catenin had strong interactions with human alphaB crystallin peptides, and the alphaB crystallin interactive sequences for these proteins were identified. The seven remaining proteins (EGF, IGF-1, TGF-beta, caspase-3, caspase-8, BCl-2, and Bcl-xL) did not interact with alphaB crystallin. The alphaB crystallin sequences that interacted with FGF-2, NGF-beta, VEGF, insulin, and beta-catenin overlapped with sequences that selectively interact with partially unfolded proteins, suggesting a common function for alphaB crystallin in chaperone activity and the regulation of cell growth and differentiation. Chaperone assays conducted with full-length alphaB crystallin and synthetic alphaB crystallin peptides confirmed the ability of alphaB crystallin to protect against the aggregation of FGF-2 and VEGF, suggesting that alphaB crystallin protects these proteins against unfolding and aggregation under conditions of stress. This is the first report in which sequences involved in interactions with regulatory proteins, including FGF-2, NGF-beta, VEGF, insulin, and beta-catenin, were identified in a small heat shock protein.
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PMID:Interactions between important regulatory proteins and human alphaB crystallin. 1748 82


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