Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ribosomal proteins (RP) L6 was previously identified as an up-regulated gene in multidrug-resistant gastric cancer cells SGC7901/ADR comparing to its parental cells SGC7901 by subtractive hybridization. The aim of this study was to explore the roles of RPL6 in multidrug resistance (MDR) in gastric cancer cells. Northern and Western blot analysis confirmed that RPL6 was overexpressed in SGC7901/ADR cells. By gene transfection, RPL6 was genetically upregulated in SGC7901 or down-regulated in SGC7901/ ADR cells. Upregulation of RPL6 was associated with enhanced resistance to multiple anticancer drugs (adriamycin, vincristine, etoposide, 5-fluorouracil and cisplatin) and to adriamycin-induced apoptosis. Downregulation of RPL6 reversed MDR and sensitized cells to adriamycin-induced apoptosis. Alteration of RPL6 showed no obvious influence on intracellular adriamycin accumulation, glutathione content and expression of glutathione S-transferase. RPL6 could upregulate Bcl-2 and downregulate Bax in cells. Together, this work demonstrates that RPL6 could regulate MDR in gastric cancer cells by suppressing drug-induced apoptosis.
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PMID:Regulation of multidrug resistance by ribosomal protein l6 in gastric cancer cells. 1584 68

Mechanisms leading to morphological changes of the small intestine during coeliac disease are not yet completely recognized, however, two main processes have been suggested recently: remodelling of mucosa by matrix metalloproteinases, and mucosal atrophy by apoptosis. The aim of this study was to analyze the expression of proteins regulating apoptosis and some markers of proliferation in the mucosa of the small intestine of children with active (ACD) and latent form (LCD) of coeliac disease (CD). Intestinal biopsies of 43 children with ACD and LCD were analyzed by standard indirect immunohistochemical technique for Fas, Fas ligand (Fas-L), tissue transglutaminase (tTG), Bcl-2, Bid, glutathione S-transferase (GST), CAS 3, CAS 8, PARP, Ki-67, Topoisomerase IIa, PCNA expression. We found significantly lower numbers of Fas-expressing enterocytes in ACD patients than in LCD patients and controls. The number of Fas-positive mucosal lymphocytes was decreased in ACD when compared with LCD. Fas-L expression in enterocytes and mucosal lymphocytes was higher in ACD and LCD compared to controls. We found significantly more Bcl-2 negative lymphocytes in ACD than in LCD and controls. Bid expression in enterocytes was higher in LCD compared to ACD and controls. In intraepithelial lymphocytes, there was higher Bid expression in LCD than in ACD and controls compared to expression in mucosal lymphocytes, where was found higher number of positive cells in controls than in ACD and LCD. Expression of CAS 8 in mucosal lymphocytes was significantly higher in ACD compared to LCD. The expression of tTG in extracellular matrix and basal lamina was significantly higher in LCD and ACD when compared to controls. Expression of tTG was higher in the group of ACD and LCD in the enterocytes and in the lymphocytes. Our findings showed that Fas/Fas-L, Bcl-2, and CAS 8 may be involved in modulation of apoptosis during CD. Increased apoptotic elimination of IEL in LCD can partially explain preservation of the normal villous architecture. Increased tTG expression may be an early sign of increased apoptosis or may be related to its role in CD pathogenesis.
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PMID:[Immunohistochemical study of the apoptotic and proliferative mechanisms in the intestinal mucosa during coeliac disease]. 1616 53

Here, we investigated the role of zinc ribbon domain-containing 1 (ZNRD1) in multidrug resistance (MDR) of leukemia cells and the possible underlying mechanisms. ZNRD1 was found overexpressed in the vincristine-induced MDR leukemia cell HL-60/vincristine moreso than its parental cell HL-60. Up-regulation of ZNRD1 expression could confer resistance of both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs on HL-60 cells and suppress Adriamycin-induced apoptosis accompanied by decreased accumulation and increased releasing amount of Adriamycin. ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. In addition, inhibition of ZNRD1 expression by RNA interference or P-gp inhibitor could partially reverse ZNRD1-mediated MDR. The further study of the biological functions of ZNRD1 may be helpful for understanding the mechanisms of MDR of leukemia and developing possible strategies to treat leukemia.
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PMID:Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2. 1637 8

An excessive and sustained increase in reactive oxygen species (ROS) production and oxidative stress have been implicated in the pathogenesis of many diseases. In the present study, we have demonstrated that 4-hydroxynonenal (4-HNE), a product of lipid peroxidation, alters glutathione (GSH) pools and induces oxidative stress in PC12 cells in culture. This increase was accompanied by alterations in subcellular ROS and glutathione (GSH) metabolisms. The GSH homeostasis was affected as both mitochondrial and extramitochondrial GSH levels, GSH peroxidase and glutathione reductase activities were inhibited and glutathione S-transferase (GST) activity was increased after 4-HNE treatment. A concentration- and time-dependent increase in cytochrome P450 2E1 (CYP 2E1) activity in the mitochondria and postmitochondrial supernatant was also observed. 4-HNE-induced oxidative stress also caused an increase in the expression of GSTA4-4, CYP2E1 and Hsp70 proteins in the mitochondria. Increased oxidative stress in PC12 cells initiated apoptosis as indicated by the release of mitochondrial cytochrome c, activation of poly-(ADP-ribose) polymerase (PARP), DNA fragmentation and decreased expression of antiapoptotic Bcl-2 proteins. Mitochondrial respiratory and redox functions also appeared to be affected markedly by 4-HNE treatment. These results suggest that HNE-induced oxidative stress and apoptosis might be associated with altered mitochondrial functions and a compromised GSH metabolism and ROS clearance.
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PMID:4-hydroxynonenal induces mitochondrial oxidative stress, apoptosis and expression of glutathione S-transferase A4-4 and cytochrome P450 2E1 in PC12 cells. 1684 8

It has been suggested that the alpha-class glutathione S-transferases (GSTs) protect various cell types from oxidative stress and lipid peroxidation (LPO). In order to examine the protective role of alpha-class GST isozyme hGSTA1-1 against doxorubicin (DOX)-induced lipid peroxidation, cytotoxicity, and apoptosis, human small cell lung cancer (SCLC) H69 cells were stably transfected with hGSTA1. Immunological and biochemical characterization of hGSTA1-transfected cells revealed the expression of functionally active hGSTA1-1 localized near the cellular plasma membranes. hGSTA1-transfected cells acquired significantly increased resistance to the DOX-induced cytotoxicity by suppressing lipid peroxidation levels in these cells. Overexpression of hGSTA1-1 in cells inhibited DOX-mediated depletion of GSH and higher GSH levels were found in DOX-treated hGSTA1-transfected cells as compared with empty vector-transfected controls. hGSTA1-1 overexpression also provided protection to cells from DOX-induced apoptosis by inhibiting phosphorylation of c-Jun-N-terminal kinases (JNK), caspase-3 activation, and by preserving the levels of anti-apoptotic protein Bcl-2. These results are consistent with the idea that the alpha-class GSTs provide protection against oxidative stress by attenuating lipid peroxidation and these enzymes can modulate signaling for apoptosis.
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PMID:Glutathione S-transferases as antioxidant enzymes: small cell lung cancer (H69) cells transfected with hGSTA1 resist doxorubicin-induced apoptosis. 1689 Jan 85

BHRF1, an early gene product of Epstein-Barr virus (EBV), is structurally and functionally homologous to Bcl-2, a cellular anti-apoptotic protein. BHRF1 has been shown to protect cells from apoptosis induced by numerous external stimuli. Nasopharyngeal carcinoma is an epithelial cancer associated closely with EBV infection. Specific proteins that might interact with and modulate the BHRF1 anti-apoptotic activity in normal epithelial cells are of interest. Therefore, a cDNA library derived from normal human foreskin keratinocytes was screened by the yeast two-hybrid system and a cellular gene encoding human vaccinia virus B1R kinase-related kinase 2 (VRK2) was isolated. Interaction between the cellular VRK2 and viral BHRF1 proteins was further demonstrated by glutathione S-transferase pull-down assays, confocal laser-scanning microscopy and co-immunoprecipitation. Analyses of VRK2-deletion mutants revealed that a 108 aa fragment at the C terminus was important for VRK2 to interact with BHRF1. For BHRF1, aa 1-18 and 89-142 were crucial in interacting with VRK2 and these two regions are counterparts of Bcl-2 homology domains 4 and 1. Overexpressed VRK2 alone showed a modest effect in anti-apoptosis and appeared to enhance cell survival in the presence of BHRF1. However, this enhancement was not observed when VRK2 was co-expressed with Bcl-2. The results indicate that human VRK2 interacts specifically with EBV BHRF1 and that the interaction is involved in protecting cells from apoptosis.
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PMID:Human cellular protein VRK2 interacts specifically with Epstein-Barr virus BHRF1, a homologue of Bcl-2, and enhances cell survival. 1696 44

The US3 protein kinase of herpes simplex virus 1 blocks apoptosis induced by replication-incompetent virus mutants, proapoptotic members of the Bcl-2 family of proteins, and by a variety of other agents that act at the premitochondrial level in the proapoptotic cascade. To define the role of US3 in blocking apoptosis at the postmitochondrial level, we investigated the US3 protein kinase in transduced cells that were either transfected with a plasmid encoding procaspase 3 or superinfected with a proapoptotic mutant virus lacking the gene encoding the infected cell protein no. 4. (i) We show that US3 blocks the proteolytic cleavage that generates active caspase 3 from the transfected zymogen procaspase 3, concomitant with inhibition of apoptosis. (ii) Studies based on detection of fluorescence emitted upon cleavage of a synthetic caspase 3 substrate showed that expression of the US3 kinase and appearance of the cleaved substrate were mutually exclusive. (iii) An affinity-purified glutathione S-transferase (GST)-US3 fusion protein, but not the inactive GST-US3(K220N) protein, phosphorylated procaspase 3 in vitro. The studies published earlier on the effect of US3 on the upstream regulatory proteins and current studies suggest that the US3 protein kinase may act on several proteins in the proapoptotic cascade to enable the virus to complete its replication.
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PMID:In transduced cells, the US3 protein kinase of herpes simplex virus 1 precludes activation and induction of apoptosis by transfected procaspase 3. 1763 20

Recently, we have reported that purified Salvia miltiorrhiza extract (PSME) could prevent myocardial infarction in vivo and myocardial ischemia/reperfusion injury in isolated rat hearts (ex vivo). The aim of this project is to determine whether PSME exerts any cardioprotective effects in vitro. The vascular smooth muscle cell line was used and the effects of the drugs were determined after inducing hypoxia. Gene expression levels of the pro-apoptotic genes Asp53, Bax, and Fas were significantly down-regulated by 0.78-, 0.82-, and 0.87-fold, respectively, and Bcl-2 was up-regulated by 0.82-fold in the PSME-treated groups as compared to the hypoxic group (P<0.05). Significant reduction in immunoreactivity of the protein products of these genes as well as least nuclear green fluorescence observed in TUNEL staining indicate the therapeutic potential of this drug. Furthermore, cardiac antioxidant enzymes assay confirmed this deduction as PSME had slight preserving effects on superoxide dismutase and catalase (0.25 +/- 0.01 vs 0.488 +/- 0.02 units/mg protein and 0.026 +/- 0.012 vs 0.076 +/- 0.01 mumol per min per mg protein, respectively; each P<0.05). No significant results were obtained with glutathione S-transferase and GSH peroxidase antioxidant tests. Our results demonstrated that PSME exerts antioxidant effects in vitro, indicating the therapeutic potential of this drug.
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PMID:Effects of purified Salvia miltiorrhiza extract on cardiac vascular smooth muscle hypoxic cells. 1765 8

In the central nervous system oxidative stress has been implicated in the pathology of several neurological disorders. The ability to withstand reactive oxygen species and oxidative stress are essential for survival and therefore all aerobic cells are endowed with chemical and enzymatic antioxidative defense systems. The purpose of the present study was to investigate the antioxidative response at the transcriptional level following exposure of primary astrocytes to a pro-oxidant, Paraquat (PQ). This was done by investigating the time-dependent expression of selected genes encoding the antioxidative enzymes Mn- and CuZn superoxide dismutase (SOD) and catalase as well as the transcription factor component AP-1. Paraquat induced the expression of Mn- and CuZn SOD, catalase and decreases the expression of c-jun (a part of AP-1). Furthermore, the gene expression profiles were investigated after exposure to PQ using a commercial cDNA membrane array containing 207 genes from key oxidative stress pathways. The gene expression pattern clearly indicated that 60 microM PQ for 48 h induces genes related to oxidative stress, detoxification, mitotic arrest, DNA repair, and apoptosis. The PQ (48 h)-induced expressions of genes identified in cDNA array were confirmed by Northern blot analysis, which revealed a statistical significant up-regulation of genes involved in oxidative stress, detoxification, and DNA repair/synthesis and includes heme oxygenase-1 (11-fold), NAD(P)H dehydrogenase (8-fold), glutathione S-transferase P (7-fold), glucose-regulated 78-kDa protein (7-fold), glucose-regulated 75-kDa protein (6-fold), and growth-arrest and DNA-damage-inducible protein 45 (4.5-fold) and minor changes for heat shock 10-kDa protein, NADPH-cytochrome P450 reductase, heme oxygenase-2, proliferating cell nuclear antigen, and Bcl-2-associated death promoter. Thus, we could demonstrate a PQ-inducible effect of the mRNA of antioxidative enzymes, as well as the mRNAs of possible enzymes involved in the protection against oxidative stress.
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PMID:Characterization of the transcriptional profile in primary astrocytes after oxidative stress induced by Paraquat. 1793 86

It is well known that insulin receptor substrates (IRS) act as a mediator for signal transduction of insulin, insulin-like growth factors, and several cytokines. To identify proteins that interact with IRS and modulate IRS-mediated signals, we performed yeast two-hybrid screening with IRS-1 as bait. Out of 109 cDNA-positive clones identified from a human placental cDNA library, two clones encoded 53BP2, p53-binding protein 2 (53BP2S), a short form splicing variant of the apoptosis-stimulating protein of p53 that possesses Src homology region 3 domain, and ankyrin repeats domain, and had been reported to interact with p53, Bcl-2, and NF-kappaB. Interaction of 53BP2S with IRS-1 was confirmed by glutathione S-transferase pull-down and co-immunoprecipitation assays in COS-7 cells and 3T3-L1 adipocytes. The Src homology region 3 domain and ankyrin repeats domain of 53BP2S were responsible for its interaction with IRS-1, whereas the phosphotyrosine binding domain and a central domain (amino acid residues 750-861) of IRS-1 were required for its interaction with 53BP2S. In CHO-C400 cells, expression of 53BP2S reduced insulin-stimulated IRS-1 tyrosine phosphorylation with a concomitant enhancement of IRS-2 tyrosine phosphorylation. In addition, the amount of the phosphatidylinositol 3-kinase regulatory p85 subunit associated with tyrosine-phosphorylated proteins, and activation of Akt was enhanced by 53BP2S expression. Although 53BP2S also enhanced Akt activation in 3T3-L1 adipocytes, insulin-induced glucose transporter 4 translocation was markedly inhibited in accordance with reduction of insulin-induced AS160 phosphorylation. Together these data demonstrate that 53BP2S interacts and modulates the insulin signals mediated by IRSs.
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PMID:53BP2S, interacting with insulin receptor substrates, modulates insulin signaling. 1796 23


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