Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expansion of CAG repeats within the coding region of target genes is the cause of several autosomal dominant neurodegenerative diseases including Huntington's disease (HD). A hallmark of HD is the proteolytic production of N-terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neurons. In this study, we used an ecdysone-inducible stable mouse neuro2a cell line that expresses truncated N-terminal huntingtin (tNhtt) with different polyglutamine length, along with mice transgenic for HD exon 1, to demonstrate that the ubiquitin-proteasome pathway is involved in the pathogenesis of HD. Proteasomal 20S core catalytic component was redistributed to the polyglutamine aggregates in both the cellular and transgenic mouse models. Proteasome inhibitor dramatically increased the rate of aggregate formation caused by tNhtt protein with 60 glutamine (60Q) repeats, but had very little influence on aggregate formation by tNhtt protein with 150Q repeats. Both normal and polyglutamine-expanded tNhtt proteins were degraded by proteasome, but the rate of degradation was inversely proportional to the repeat length. The shift of the proteasomal components from the total cellular environment to the aggregates, as well as the comparatively slower degradation of tNhtt with longer polyglutamine, decreased the proteasome's availability for degrading other key target proteins, such as p53. This altered proteasomal function was associated with disrupted mitochondrial membrane potential, released cytochrome c from mitochondria into the cytosol and activated caspase-9- and caspase-3-like proteases. These results suggest that the impaired proteasomal function plays an important role in polyglutamine protein-induced cell death.
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PMID:Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. 1133 15

The inhibitor of apoptosis (IAP) family of anti-apoptotic proteins regulate programmed cell death and/or apoptosis. One such protein, X-linked IAP (XIAP), inhibits the activity of the cell death proteases, caspase-3, -7, and -9. In this study, using constitutively active mutants of caspase-3, we found that XIAP promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. The XIAP mutants, which cannot interact with caspase-3, had little or no activity of promoting the degradation of caspase-3. RING finger mutants of XIAP also could not promote the degradation of caspase-3. A proteasome inhibitor suppressed the degradation of caspase-3 by XIAP, suggesting the involvement of a ubiquitin-proteasome pathway in the degradation. An in vitro ubiquitination assay revealed that XIAP acts as a ubiquitin-protein ligase for caspase-3. Caspase-3 was ubiquitinated in the presence of XIAP in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. Finally, the RING finger mutants of XIAP were less effective than wild-type XIAP at preventing apoptosis induced by overexpression of either active-form caspase-3 or Fas. These results demonstrate that the ubiquitin-protein ligase activity of XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect.
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PMID:Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. 1144 97

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins and cell cycle control. Dysregulating the degradation of such proteins should have profound effects on tumor growth and causes cells to undergo apoptosis. The aims of this study are to evaluate the ubiquitin-proteasome pathway in gastric cancer and the potential role of pharmacological inhibition of proteasome on induction of apoptosis in gastric cancer cells. Gastric cancer cell lines AGS (p53 wild-type) and MKN-28 (p53 mutant) were treated with proteasome inhibitor MG132. The results showed that MG132 inhibited cell proliferation in AGS and MKN-28 cells in a time- and dose-dependent manner. The inhibition of cell proliferation was caused by apoptosis which was also time- and dose-dependent. AGS cells were more responsive to MG132 than MKN-28 cells. Induction of apoptosis was preceded by the activation of caspase-3, as measured by a colorimetric caspase-3 cellular activity and Western blotting of the cleavage of caspase-3 and its substrate PARP. Activation of caspase-7 was also exhibited. In addition, z-VAD-fmk, a broad spectrum caspase inhibitor, reversed apoptosis induced by MG132 in AGS and MKN28 cells. Although z-DEVD-fmk, a specific caspase-3 inhibitor, suppressed MG132-induced apoptosis in MKN28 cells, it only partially rescued the apoptotic effect in AGS cells. Caspase-3 activation was the result of release of cytochrome c from mitochondria into the cytosol, as a consequence of upregulation of bax. There were overexpressions of all the proteasome-related proteins p53, p21(waf1) and p27(kip1) at 4 hr after proteasome inhibition which was identified by the accumulation of ubiquitin-tagged proteins. This was accompanied by accumulation of cells at G(1) phase. Our present study suggests that inhibition of proteasome function in gastric cancer cells induces apoptosis and proteasomal inhibitors have potential use as novel anticancer drugs in gastric cancer.
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PMID:Inhibition of proteasome function induced apoptosis in gastric cancer. 1147 51

Proteasome inhibitors were shown previously to induce mitochondria-independent and caspase-3-dependent apoptosis in human glioma cell lines by unknown mechanisms. Here, we showed that treatment with proteasome inhibitors, lactacystin or acetyl-leucinyl-leucinyl-norleucinal, led to elevation of the steady-state c-Myc protein but not c-myc mRNA, suggesting the accumulation of c-Myc protein by proteasome inhibitors. In addition, the marked association of c-Myc protein with ubiquitin by treatment with proteasome inhibitors indicated the involvement of proteasome in c-Myc proteolysis and the stabilization of c-Myc protein by proteasome inhibitors in vivo. The expression of Fas (also termed CD95 or APO-1) mRNA, if analyzed by reverse transcriptase polymerase chain reaction assay, was found to occur constitutively, and increased slightly by the treatment with proteasome inhibitors. In contrast, the expression of Fas ligand (FasL) mRNA was markedly induced temporarily before the activation of caspase-3 by the treatment. Agonistic anti-Fas antibody (CH11) induced apoptotic cell death, suggesting the presence of a functional Fas receptor. In addition, proteasome inhibitor-induced apoptosis was prevented by the addition of antagonistic anti-FasL antibody (4A5) or z-IETD.fmk, a potent inhibitor of caspase-8, indicating the involvement of the Fas receptor-ligand apoptotic signaling system in proteasome inhibitor-mediated apoptosis. Thus, it is suggested that proteasome inhibitors cause the accumulation of c-Myc protein which induces transiently FasL message to stimulate the Fas receptor-ligand apoptotic signaling pathway.
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PMID:Proteasome inhibitors induce Fas-mediated apoptosis by c-Myc accumulation and subsequent induction of FasL message in human glioma cells. 1152 96

FAF1 is a Fas-binding protein without typical death domain. Instead, FAF1 has several domains found in proteins of ubiquitination pathway. Transient overexpression of hFAF1 in BOSC23 cells caused membrane blebbing and cell body condensation which were characteristics of apoptosis. Subsequent analysis revealed that overexpression of hFAF1 induced nuclear condensation, appearance of phosphatidylserines in the outer leaflet of the cellular membrane, and caspase 3 activation. The apoptotic potential of hFAF1 required downstream ubiquitin homologous domain (UB2) and adjacent nuclear localization signal but not the Fas-binding domain. Our data showed that mere intrinsic overexpression of hFAF1 initiated apoptosis in the absence of any extrinsic death signal in BOSC23 cells.
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PMID:Apoptosis induced by human Fas-associated factor 1, hFAF1, requires its ubiquitin homologous domain, but not the Fas-binding domain. 1152 3

Chronic systemic complex I inhibition caused by rotenone exposure induces features of Parkinson's disease (PD) in rats, including selective nigrostriatal dopaminergic degeneration and formation of ubiquitin- and alpha-synuclein-positive inclusions (Betarbet et al., 2000). To determine underlying mechanisms of rotenone-induced cell death, we developed a chronic in vitro model based on treating human neuroblastoma cells with 5 nm rotenone for 1-4 weeks. For up to 4 weeks, cells grown in the presence of rotenone had normal morphology and growth kinetics, but at this time point, approximately 5% of cells began to undergo apoptosis. Short-term rotenone treatment (1 week) elevated soluble alpha-synuclein protein levels without changing message levels, suggesting that alpha-synuclein degradation was retarded. Chronic rotenone exposure (4 weeks) increased levels of SDS-insoluble alpha-synuclein and ubiquitin. After a latency of >2 weeks, rotenone-treated cells showed evidence of oxidative stress, including loss of glutathione and increased oxidative DNA and protein damage. Chronic rotenone treatment (4 weeks) caused a slight elevation in basal apoptosis and markedly sensitized cells to further oxidative challenge. In response to H2O2, there was cytochrome c release from mitochondria, caspase-3 activation, and apoptosis, all of which occurred earlier and to a much greater extent in rotenone-treated cells; caspase inhibition provided substantial protection. These studies indicate that chronic low-grade complex I inhibition caused by rotenone exposure induces accumulation and aggregation of alpha-synuclein and ubiquitin, progressive oxidative damage, and caspase-dependent death, mechanisms that may be central to PD pathogenesis.
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PMID:An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. 1217 98

Exisulind and its analogues are inhibitors of cyclic GMP phosphodiesterases (PDEs) that have been shown to activate and induce protein kinase G, resulting in the induction of apoptosis in colon cancer cells. These drugs also reduce beta-catenin protein levels and decrease cyclin D1 mRNA levels in SW480 cells. Herein we report on studies pertaining to exisulind regulation of beta-catenin levels and activity in colon tumor cells. Exisulind and its higher-affinity PDE analogues, (Z)-5-fluoro-2-methyl-(4-pyridylidene)-3-(N-benzyl)-indenylacetamide hydrochloride (CP461) and (Z)-1H-indene-3-acetamide, 5-fluoro-2-methyl-N-(phenylmethyl)-1-[(3,4,5-trimethoxyphenyl)methylene] (CP248), reduced beta-catenin, including the nuclear beta-catenin in SW480 cells (EC(50) approximately 200 microM, 1 microM, and <1 microM, respectively). The 50% reduction of beta-catenin was seen in 8-14 hr. There was no change in beta-catenin mRNA. Exisulind-induced beta-catenin reduction was blocked by the proteasomal inhibitor MG132 (Z-leu-Leu-Leu-CHO), indicating that the effect of exisulind involved ubiquitin-proteasomal degradation. A consequence of reduced beta-catenin in SW480 cells was that exisulind, CP461, and CP248 caused a concentration- and time-dependent decrease in cyclin D1 levels (EC(50) approximately 300 microM, 1 microM, and <1 microM, respectively) in 4 hr. The effect was via decreased cyclin D1 mRNA levels. Exisulind-induced degradation of beta-catenin was not blocked by the inhibition of caspase-3 activity and/or apoptosis, and some SW480 cells showed a reduction in beta-catenin levels before the appearance of early apoptosis indicators. Expression of the N-terminal 170 amino acid fragment of beta-catenin reduced the effects of beta-catenin degradation, cyclin D1 reduction, and the apoptosis response to exisulind. These results indicate that exisulind-induced beta-catenin degradation precedes the induction of apoptosis and that the down-regulation of inappropriate beta-catenin-activated genes accounts in part for the pro-apoptotic effects of exisulind and CP461 in colon tumor cells.
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PMID:Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation. 1239 15

Programmed cell death (apoptosis) is crucial for thymocyte development. We analyzed the role of the ubiquitin (Ub)-proteasome pathway in dexamethasone-triggered and TCR-mediated apoptosis in fetal thymic organ culture (FTOC). Proteasome activity was increased in apoptotic thymocytes, as visualized by active-site labeling of proteasomal beta subunits. The activity of deubiquitinating enzymes in murine apoptotic thymocytes was likewise examined by active-site labeling. We show that the deubiquitinating enzyme USP7 (HAUSP) is proteolytically processed upon dexamethasone-, gamma-irradiation-, and antigen-induced cell death. Such processing of HAUSP does not occur in caspase 3-/- thymocytes, or upon pretreatment of wild type thymocytes with the general caspase inhibitor ZVAD-fmk. Thus, our results suggest that thymocyte apoptosis leads to modification of deubiquitinating enzymes by caspase activity and may provide an additional link between the ubiquitin-proteasome pathway and the caspase cascade during programmed cell death.
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PMID:The ubiquitin-proteasome pathway in thymocyte apoptosis: caspase-dependent processing of the deubiquitinating enzyme USP7 (HAUSP). 1241 94

Parkinson's disease (PD) is morphologically characterized by progressive loss of neurons in the substantia nigra pars compacta (SNpc) and other subcortical nuclei associated with intracytoplasmic Lewy bodies and dystrophic (Lewy) neurites mainly in subcortical nuclei and hippocampus und, less frequently in cerebral cortex. SN cell loss is significantly related to striatal dopamine (DA) deficiency as well as to both the duration and clinical severity of disease, The two major clinical subtypes of PD show different morphologic lesion patterns: the akinetic-rigid form has more severe cell loss in the ventrolateral part of SN with negative correlation to DA loss in the posterior putamen, and motor symptoms related to overacitivty of the GABAergic "indirect" motor loop, which causes inhibition of the glutamatergic thalamocortical pathway and reduced cortical activation. The tremor-dominant type shows more severe cell loss in the medial SNpc and retrorubal field A 8, which project to the matrix of the dorsolateral striatum and ventromedial thalamus, thus causing hyperactivity of thalamomotor and cerebellar projections. These and experimental data suggesting different pathophysiological mechanisms for the major clinical subtypes of PD may have important therapeutic implications. Lewy bodies, the morphologic markers of PD, are composed of hyperphosphorylated neurofilament proteins, lipids, redox-active iron, ubiquitin, and alpha-synuclein, showing a continuous accumulation in the periphery and of ubiquitin in the central core. Alpha-synuclein, is usually unfolded in alpha-helical form. By gene mutation, environmental stress or other factors it can be transformed to beta-folding which is sensible to self-aggregation in filamentous fibrils and formation of insoluble intracellular inclusions that may lead to functional disturbances and, finally, to death of involved neurons. While experimental and tissue culture studies suggest that apoptosis, a genetically determined form of programmed cell death, represents the most common pathway in neurodegeneration, DNA fragmentation, overexpression of proapoptotic proteins and activated caspase-3, the effector enzyme of the terminal apopoptic cascade, have only extremely rarely been detected in SN of PD brains. This is in accordance with the rapid course of apoptotis and the extremely slow progression of the neurodegenerative process in PD. The biological role of Lewy bodies and other intracellular inclusions, the mechanisms of the intracellular aggregation of insoluble protein deposits, and their implication for cellular dysfunction resulting in neurodegeneration and cell demise are still unresolved. Further elucidation of the basic molecular mechanisms of cytoskeletal lesions will provide better insight into the pathogenesis of neurodegeneration in PD and related disorders.
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PMID:Recent developments in the pathology of Parkinson's disease. 1245 78

The ubiquitin-proteasome pathway is an intracellular protein degradation pathway responsible for degradation of many regulatory proteins that must be rapidly eliminated normally. Some recent studies reported that a proteasome dysfunction was involved in the pathogenesis of neurodegenerative diseases. Thus, there is now considerable interest in the possible role of proteasome in this regard. Here we show that inhibition of proteasomal function by Lactacystin-induced cell death in a neuronal differentiated Neuro2a (nN2a) cell line but not in an undifferentiated Neuro2a (N2a) cell line. Cell death was accompanied by both the activation of c-Jun N-terminal kinase, p38 and caspase-3. A pan-caspase inhibitor, Z-VAD-FMK, or SB203580, a p38 inhibitor could not inhibit cell death induced by Lactacystin, whereas nN2a cell lines with stable expression of the dominant negative mutant of c-Jun N-terminal kinase showed a remarkable suppression of cell death. Lactacystin-induced cell death is mediated through the c-Jun N-terminal kinase pathway but not the caspase-dependent pathway in a nN2a cell line. Our results shed light on the association among the proteasomal dysfunction, JNK pathway and neuronal cell death, leading to the elucidation of its possible role in the pathogenesis of neurodegenerative diseases.
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PMID:c-Jun N-terminal kinase pathway mediates Lactacystin-induced cell death in a neuronal differentiated Neuro2a cell line. 1248 Jan 74


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