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)

Apoptosis or programmed cell death is essential in the process of controlling lymphocyte growth and selection. We identified proteins that are involved in anti-IgM antibody-mediated apoptosis using a subclone of the human Burkitt lymphoma cell line BL60. Apoptosis-associated proteins were detected by high resolution two-dimensional gel electrophoresis on a micropreparative scale. Comparison of the high resolution two-dimensional gel electrophoresis protein patterns from apoptotic and non-apoptotic cells showed differences in approximately 80 spots including protein modifications. Analysis of the predominantly altered proteins was performed by internal Edman microsequencing and/or by peptide mass fingerprinting using matrix-assisted laser desorption/ionization mass spectrometry. Analysis was significantly improved by using new micropreparative high resolution two-dimensional gels employing high protein concentrations. The following 12 apoptosis-associated proteins were identified: heterogeneous nuclear ribonucleoprotein (hnRNP) A1, hnRNP C1/C2, FUSE-binding protein, dUTPase, lymphocyte-specific protein LSP1, UV excision repair protein RAD23 homologue B (HHR23B), 60 S acidic ribosomal protein P0 (L10E), heterochromatin protein 1 homologue alpha (HP1alpha), nucleolin, lamin, neutral calponin, and actin. Fragmentation of actin, hnRNP A1, hnRNP C1/C2, 60 S acidic ribosomal protein P0, lamin, and nucleolin could be inhibited by benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone, a selective irreversible inhibitor of CPP32 (caspase 3).
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PMID:Identification of apoptosis-associated proteins in a human Burkitt lymphoma cell line. Cleavage of heterogeneous nuclear ribonucleoprotein A1 by caspase 3. 977 22

We obtained evidence that increased stability of nucleophosmin/B23 is involved in antiapoptotic effect of ras during serum deprivation. Nucleophosmin/B23 in serum-deprived (0% serum) NIH-3T3 cells was found to be highly unstable with a half-life less than 4 h. In contrast, nucleophosmin/B23 in serum-deprived ras-transformed (RAS-3T3) cells was as stable as that in serum-supplemented NIH-3T3 or RAS-3T3 cells. Treatment of RAS-3T3 cells with nucleophosmin/B23 antisense oligomer significantly potentiated the apoptosis induced by serum deprivation. Much less caspase-3 activity was noted in the lysate derived from serum-deprived RAS-3T3 cells compared with that in the lysate of serum-deprived NIH-3T3 cells. Cell permeable caspase-3 inhibitor added in the medium blocked the decrease of nucleophosmin/B23 and apoptosis induced by serum deprivation in NIH-3T3 cells. The inhibitor, on the other hand, promoted significant decrease of nucleolin/C23 in NIH-3T3 cells during serum deprivation. Unlike nucleolin/C23, down-regulation of nucleophosmin/B23 was thus not proliferation-dependent but caspase-3- and apoptosis-dependent. Our results indicate important relationships among ras, nucleophosmin/B23, activation of caspase-3, and induction of apoptosis.
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PMID:Increased stability of nucleophosmin/B23 in anti-apoptotic effect of ras during serum deprivation. 1112 22

The aim of our study was to explore the antiproliferative and pro-apoptotic action of roscovitine (ROSC) on human breast cancer MCF-7 cells. We examined the effect of ROSC on cell proliferation, cell cycle progression, nucleolar morphology, posttranslational modifications of histones as well as on induction of apoptosis. The effects of ROSC on the argyrophilic nucleolar organizer regions (AgNORs) and nucleolar RNA of MCF-7 cells were marked: ROSC treatment changed the pattern of AgNORs in a time-dependent manner. The disintegration of nucleoli manifested by increasing number of nucleolar fragments already began at 6 hr posttreatment. This was accompanied by a redistribution of the nucleolin from the nucleolus beginning after 6 hr and preceded a decrease of histone acetylation and phosphorylation. Inhibition of DNA synthesis and accumulation of G(2)/M-arrested cells starting 6 hr posttreatment coincided with a strong increase of the p53 level and with an appearance of a few cells committed to undergo apoptosis. However, all these changes preceded the main wave of apoptosis, which occurred after 24 hr ROSC treatment as assessed by determination of the frequency of Annexin binding, activation of caspases as well as of DNA fragmentation. Onset of PARP-1 cleavage detected by immunoblotting and by immunohistochemistry 6 hr or 9 hr posttreatment, respectively, preceded for a few hours the DNA fragmentation detected in situ by TUNEL assay. Reconstitution of MCF-7 cells with caspase-3 did not change the kinetics of ROSC-induced apoptosis. Our results show that disintegration of nucleoli is an early marker of ROSC-induced changes. Cell cycle arrest precedes the main wave of apoptosis.
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PMID:Rapid onset of nucleolar disintegration preceding cell cycle arrest in roscovitine-induced apoptosis of human MCF-7 breast cancer cells. 1284 42

Lipopolysaccharide (LPS) is a complex glycolipid composed of a hydrophilic polysaccharide and a hydrophobic domain that is responsible for the biological activity of LPS. There are many reports about LPS stimulation, and many activated proteins have been detected after LPS stimulation in various cell types. Furthermore, most of the LPS signaling pathways are clear. However, we were interested in examining the changes of LPS-induced total cytosolic proteins expression and the LPS signaling pathway by the proteomics technique during LPS-induced macrophage activation. Our study employed two-dimensional gel electrophoresis and mass spectrometry to analyze the proteins involved in LPS-induced activation in RAW 264.7 cells. We found 11 protein spots whose expression was different between untreated cells and LPS-treated cells. Ten protein spots were identified, seven of which, tubulin beta-4 chain (49.6 kDa, pI 4.78), nucleophosmin (32.6 kDa, pI 4.62, two spots), 40S ribosomal protein SA (P40) (32.7 kDa, pI 4.74), transforming protein RhoA (21.8 kDa, pI 5.83), nucleolin (76.6 kDa, pI 4.69), and T-complex protein 1 zeta subunit (58 kDa, pI 6.63) were down-regulated, and three of which, nucleophosmin (32.6 kDa, pI 4.62, two spots) and proteosome subunit alpha type-1 (29.5 kDa, pI 6.00), were up-regulated. The suppression of the proteolytic degradation of nucleophosmin was associated with LPS-induced RAW 264.7 cell activation. Cleaved caspase-3 decreased, thus it might be involved in proteolysis of nucleophosmin in LPS-induced macrophage activation. Our study also demonstrated that there was no change of the expression of nucleophosmin at the mRNA level.
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PMID:Proteomic analysis of macrophages stimulated by lipopolysaccharide: Lipopolysaccharide inhibits the cleavage of nucleophosmin. 1660 39

Human erythrocytes exposed to appropriate concentrations of H(2)O(2) for 1h became susceptible to the binding and phagocytosis by macrophages. The binding was inhibited by anti-band 3 serum and prevented by pretreatment of erythrocytes with a polylactosamine-cleaving enzyme endo-beta-galactosidase, indicating that polylactosaminyl sugar chains of band 3 are recognized by macrophages. The macrophage receptor involved was suggested to be nucleolin, a recently identified macrophage surface protein recognizing sialylpolylactosaminyl-chain clusters on early apoptotic cells, because anti-nucleolin antibody and a soluble form of recombinant nucleolin blocked the recognition. Treatment of erythrocytes with caspase inhibitors Z-VAD-fmk or Z-DQMD-fmk (caspase 3 selective) before the oxidation resulted in lowered binding of the oxidized erythrocytes to macrophages, suggesting that actions of caspases, particularly those of caspase 3, are prerequisite for the membrane changes leading to band 3 aggregation. Moreover, the cytosolic caspase 3 was found to be activated by H(2)O(2), and the extent of the activation correlated well with the susceptibility of the oxidized erythrocytes to the macrophage recognition. These results suggest that oxidative stress renders the erythrocytes susceptible to clearance by macrophages through activation of caspases leading to band 3 aggregation.
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PMID:Clearance of oxidized erythrocytes by macrophages: involvement of caspases in the generation of clearance signal at band 3 glycoprotein. 1785 72

Neochamaejasmin A ( 1), a biflavonoid isolated from the roots of a traditional Chinese medicine, Stellera chamaejasme L., was shown to inhibit cellular (3)H-thymidine incorporation (IC 50 12.5 microg/mL) and subsequent proliferation of human prostate cancer LNCaP cells. Treatment of LNCaP cells with low doses of 1 (< or =6.25 microg/mL) suppressed DNA-binding activities of the transcription factors NFkappaB and AP-1 to the promoter of cyclin D and also inhibited expression of the cell cycle regulatory proteins cyclin D, proliferating cell nuclear antigen, and nucleolin, thus arresting cells in G 1 phase of the cell cycle. A lengthy exposure with higher doses of 1 (> or =12.5 microg/mL) revealed the production of reactive oxygen species, dissipation of the mitochondrial membrane potential, up-regulation of cyclin-dependent kinase inhibitor p21, and induction of cell apoptosis. An aggregation of Fas-procaspase 8-procaspase 3 and p21-procaspase 3 proteins by coimmunoprecipitation, immunoblotting analysis, and MALDI-mass spectrometry indicated the involvement of Fas and p21 in 1-mediated cytotoxicity, and pretreatment of cells with antisense FasL oligonucleotides partially abolished apoptosis. Thus, 1 blocked cell cycle progression at the G 1 phase by activating the p21 protein and ultimately promoting the Fas-caspase 8-caspase 3 apoptotic machinery.
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PMID:Involvement of p21 and FasL in induction of cell cycle arrest and apoptosis by neochamaejasmin A in human prostate LNCaP cancer cells. 1838 Apr 77

The mechanism of macrophage recognition of oxidatively damaged cells was investigated. Jurkat T cells exposed to various concentrations of H(2)O(2) were bound and phagocytosed by macrophages. The cells exposed to 0.1 mM H(2)O(2) were best bound. The cell-surface ligands recognized by macrophages were suggested to be sialylpolylactosaminyl sugar chains of a major sialoglycoprotein CD43 because 1) the cell binding was inhibited by oligosaccharides containing sialylpolylactosaminyl chains, and their inhibitory activity was destroyed by a polylactosamine-cleaving enzyme endo-beta-galactosidase, and by neuraminidase; 2) the oxidized Jurkat cells pretreated with either glycosidase or with anti-CD43 antibody were not bound. The macrophage receptor involved in the binding was suggested to be cell-surface nucleolin because 1) anti-nucleolin antibody inhibited the binding; 2) nucleolin-transfected HEK293 cells bound the oxidized cells; and 3) this binding was inhibited by anti-nucleolin antibody and by anti-CD43 antibody. CD43 on oxidized Jurkat cells tended to form clusters in good accordance with their susceptibility to the macrophage binding. CD43 clustering and the oxidized-cell binding to macrophages were prevented by a caspase inhibitor Z-VAD-fmk, suggesting that the oxidized and bound cells were undergoing apoptosis. Indeed, caspase-3 activity of Jurkat cells increased by the oxidation. These results suggest that moderately oxidized cells undergo apoptosis and are recognized by macrophages as early apoptotic cells.
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PMID:Clearance of oxidatively damaged cells by macrophages: recognition of glycoprotein clusters by macrophage-surface nucleolin as early apoptotic cells. 1933 85

Although heat shock protein 70 (Hsp70) has been shown to markedly inhibit H(2)O(2)-induced apoptosis in C2C12 cells, and nucleolin/C23 has also been implicated in apoptosis, the relationship of these two molecules is still largely unknown. The aim of the current study was to investigate the potential involvement of nucleolin/C23 in the antiapoptotic mechanism of Hsp70. We found that primary cultures of neonatal rat cardiomyocytes underwent apoptosis upon H(2)O(2) treatment, and in these cells nucleolin/C23 protein was highly unstable and had a half-life of less than 4 h. However, transfection with Hsp70 greatly stabilized nucleolin/C23 and also protected the cells from H(2)O(2)-induced apoptosis. When nucleolin/C23 was knocked down with an antisense oligomer, H(2)O(2)-induced apoptosis became more severe, even in Hsp70-overexpressed cells, demonstrating an essential role of nucleolin/C23 in the antiapoptotic effects of Hsp70. Similar results were obtained by both nuclear morphology observation and caspase-3 activity assay. Therefore, these data provide evidence that nucleolin/C23 is an essential downstream effecter of Hsp70 in the protection of cardiomyocytes against oxidative stress-induced apoptosis.
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PMID:Nucleolin/C23 mediates the antiapoptotic effect of heat shock protein 70 during oxidative stress. 2005 Sep 22

Attachment of stone crystals to tubular epithelium may initiate kidney stone formation. We previously reported that apical nucleolin related protein (NRP) expression during mitosis enhance attachment of Ca oxalate monohydrate crystals (COM). Some forms of injury may also increase affinity for crystals. We examined changes in subcellular localization of NRP during the course of cisplatin-induced apoptosis in cultured inner medullary collecting duct cells. Caspase-3 activation and chromatin condensation followed by nuclear fragmentation occurred after 20 h exposure to cisplatin, indicating the development of apoptosis. Cells were fixed without permeabilization and stained for surface NRP. Cells with condensed chromatin showed little or no cytoplasmic or apical NRP. Those at an early stage of nuclear fragmentation had cytoplasmic but not apical NRP and cells with advanced nuclear fragmentation were positively stained for apical NRP. Membrane proteins isolated by apical biotinylation and precipitated with avidin were analyzed by Western blot. Apical NRP was markedly increased after cisplatin compared to control, while expression of the apical marker, GP-135, and other putative attachment protein were unchanged. Hyaluronic acid was decreased. Cultures with apoptotic cells demonstrated increased adherence of COM that was inhibited by the polyanion (poly)aspartic acid. We conclude that pre-existing apoptotic injury may promote calcium oxalate crystals attachment to renal tubular epithelium via apical NRP expression.
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PMID:Induction of apoptosis with cisplatin enhances calcium oxalate crystal adherence to inner medullary collecting duct cells. 2007 9

Angiotensin II (Ang II) is a key proapoptotic factor in fibrotic tissue diseases. However, the mechanism of Ang-II-induced cell death in endothelial cells has not been previously elucidated. Using the neutral comet assay and specific receptor antagonists and agonists, we found that Ang-II-mediated apoptosis in primary pulmonary endothelial cells required the AT2 receptor. Ang II caused cytochrome c release from the mitochondria concurrent with caspase-3 activation and DNA fragmentation, and apoptosis was suppressed by an inhibitor of Bax-protein channel formation, implicating mitochondrial-mediated apoptosis. There was no evidence that the extrinsic apoptotic pathway was involved, because caspase-9, but not caspase-8, was activated by Ang-II treatment. Apoptosis required phosphoprotein phosphatase activation, and inhibition of the SHP-2 phosphatase (encoded by Ptpn11) blocked cell death. Reduced levels of anti-apoptotic Bcl-2-family members can initiate intrinsic apoptosis, and we found that Ang-II treatment lowered cytosolic Bcl-x(L) protein levels. Because the protein nucleolin has been demonstrated to bind Bcl-x(L) mRNA and prevent its degradation, we investigated the role of nucleolin in Ang-II-induced loss of Bcl-x(L). RNA-immunoprecipitation experiments revealed that Ang II reduced the binding of nucleolin to Bcl-x(L) mRNA in an AU-rich region implicated in instability of Bcl-x(L) mRNA. Inhibition of SHP-2 prevented Ang-II-induced degradation of Bcl-x(L) mRNA. Taken together, our findings suggest that nucleolin is a primary target of Ang-II signaling, and that Ang-II-activated SHP-2 inhibits nucleolin binding to Bcl-x(L) mRNA, thus affecting the equilibrium between pro- and anti-apoptotic members of the Bcl-2 family.
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PMID:Angiotensin-II-induced apoptosis requires regulation of nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells. 2040 88


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