Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An Epstein-Barr virus protein associated with the restricted component of the early antigen complex was characterized in this study. This protein was of particular interest because of its homology to polyoma middle T antigen and to the product of the bcl-2 oncogene. The results from this study reveal that this protein had a number of unusual properties in comparison with other polypeptides associated with the early antigen complex. For example, the synthesis of this membrane-associated antigen was regulated by the cell cycle, and its expression was compatible with cell survival. Functional studies reveal that immunoprecipitates containing this protein exhibited a threonine-serine-specific protein kinase activity. The results suggest that this protein might function in both the immortalization and replication cycles of this virus.
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PMID:Protein kinase activity associated with a cell cycle regulated, membrane-bound Epstein-Barr virus induced early antigen. 215 54

Activation of the multicomponent interleukin-2 receptor (IL-2R) complex leads to a rapid increase in tyrosine phosphorylation of a number of cellular proteins including the IL-2R beta and IL-2R gamma chains of the IL-2R and the RAF-1 serine threonine kinase. In addition, phosphatidylinositol 3-kinase (PI-3K) protein and activity can be immunoprecipitated with anti-phosphotyrosine and anti-IL-2R beta antibodies from IL-2-activated but not resting T lymphocytes. We have demonstrated that the SH2 (SRC homology 2) domains of the 85 kDa subunit of PI-3K are sufficient to mediate binding of the PI-3K complex to tyrosine phosphorylated, but not non-phosphorylated IL-2R beta, suggesting that tyrosine phosphorylation is an integral component of the activation of PI-3K by the IL-2R. Since none of the members of the IL-2R complex contains an intrinsic tyrosine kinase domain, IL-2-induced tyrosine phosphorylation must be the consequence of activation of intracellular tyrosine kinases. SRC family members including lck, lyn and fyn have been demonstrated to associate with IL-2R beta through binding of the kinase domain to the acidic domain of IL-2R beta. However, we have demonstrated that the serine rich (SD) region of the cytosolic domain of IL-2R beta is also required for association of a tyrosine kinase with the IL-2R complex and that IL-2 can induce proliferation and tyrosine phosphorylation in cell lines which lack the known SRC family kinases expressed by T lymphocytes. Thus members of other kinase families besides SRC may also be involved in mediating IL-2 signal transduction. Biochemical studies and studies of cells expressing mutant IL-2 receptors indicate that IL-2-induced tyrosine kinase activation initiates a complex signaling cascade. The cascade includes SRC family kinase members such as lck, fyn, and lyn, activation of Raf-1 and PI-3K, and ras, and increased expression of the fos, fra-1, and jun protooncogenes. In addition, ligation of the IL-2R leads to rapid increases in myc expression and more delayed increases in the expression of the cdc2 and cdk2 kinases and the cyclins through a tyrosine phosphorylation independent pathway. Whether other biochemical processes initiated by IL-2R ligation, including activation of the MAP2, p70S6 and p90RSK serine threonine kinases, activation of NF-kappa B, and increased expression of Raf-1, Pim-1, bcl-2, IL-2R alpha and IL-2R beta, are consequences of the IL-2-induced tyrosine kinase cascade remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transmembrane signaling by the interleukin-2 receptor: progress and conundrums. 826 Jun 51

We have studied the regulation of growth and apoptosis in murine BA/F3 cells stably expressing cytoplasmic deletion mutants of the human interleukin-4 receptor (hIL-4R). Previously, we showed that BA/F3 cell transfectants expressing a cytoplasmic deletion mutant of the hIL-4R that lacks the region between Thr(462) and Ala(580), referred to as delta R3, fails to proliferate in the presence of hIL-4. Here we report that supertransfection of delta R3-expressing cells with a constitutively active murine bcl-2 gene results in prolonged survival of the delta R3/bel-2 double transfectants in the absence of cytokines. More importantly, however, the constitutive expression of Bcl-2 restored their capacity to grow permanently with hIL-4. This may provide an explanation for the discrepancy with previous reports showing growth mediation by hIL-4R truncated at position 367.
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PMID:IL-4-dependent proliferation of BA/F3 cells expressing a growth-negative mutant of the human IL-4 receptor is restored by enforced expression of Bcl-2. 861 8

There are two points (brake-points) through which the cell must pass before it can enter cell division. Progress through each brake-point requires the presence of an active cyclin-dependent kinase (Cdk). There are specific cyclins to activate the Cdk's at different parts of the cell cycle. Activation of the cyclin-Cdk complex is tightly regulated by the phosphorylation state of the Cdk. Exogenous growth stimulators (hormones, growth factors, and cytokines) all work through an intracellular kinase cascade that drives the production and activation of early nuclear proteins that, in turn, induce transcription of the genes for cyclins, Cdk's, and other cell cycle regulators. Retinoblastoma protein regulates cell division by inactivating specific growth-promoting proteins. Therefore, mutation of the Rb gene can lead to uncontrolled cell division and thus promotion of transformed cells. p53 protein will prevent replication of cells with damaged DNA. Hence, transformed cells can only readily progress to tumors if the p53 gene is mutated in a manner that inactivates the protein product. Members of the bcl-2 family act, in homodimers and heterodimers, to shunt cells either into cell division or into apoptosis. Understanding the mechanisms by which the balance of cell cycle: apoptosis can be manipulated will lead to new ways of controlling abnormal cellular growth. Most aspects of cellular function reflect changes in phosphorylation of critical serine, threonine, and tyrosine residues on the relevant regulatory proteins. The kinases the phosphatases involved are themselves under tight control.
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PMID:The cell cycle and regulation of cancer cell growth. 865 73

Okadaic acid, an inhibitor of serine/threonine protein phosphatases 1 and 2A has been shown to cause mitotic arrest and cell death of HL-60 and K562 cells. HL-60 cells express Bcl-2 and little or no Bcl-X(L), while K562 expresses Bcl-X(L) but not Bcl-2. Since phosphorylation/dephosphorylation reactions have been suggested to be involved in the regulation of Bcl-2, we planned to investigate whether the expression of Bcl-2, Bcl-X(L) and Bax, a protein that antagonizes the antiapoptotic function of Bcl-2, are regulated in myeloid leukemia cell lines (K562, KU812 and HL-60) treated with okadaic acid. Our results indicate that exposure of all three leukemic cell lines to nanomolar concentrations of okadaic acid causes a loss of viability by activation of an apoptotic process accompanied by a marked decrease in the expression of Bcl-2, Bcl-X(L) and Bax at both mRNA and protein level, but not of c-fos, vimentin and epsilon-globin, ruling out a non-specific effect of okadaic acid. Furthermore, constitutive expression of either Bcl-X(L) or Bcl-2 by gene transfer inhibited apoptosis triggered by okadaic acid in K562 cells. Thus, we suggest that protein phosphatases may be involved in maintaining the expression of bcl-2 family genes as part of the survival machinery of the cell.
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PMID:Apoptosis of human myeloid leukemia cells induced by an inhibitor of protein phosphatases (okadaic acid) is prevented by Bcl-2 and Bcl-X(L). 920 72

Bax is a member of the Bcl-2 protein family with proapoptotic properties. The proteins of this family contain three highly conserved regions termed BH1, BH2, and BH3 as well as a hydrophobic COOH-terminal domain, which is responsible for the membrane attachment of the proteins. We have expressed human Bax truncated of the 20 amino acid COOH-terminal hydrophobic domain to obtain large amounts of soluble protein suitable for biochemical and structural studies. The truncated protein was expressed as a glutathione S-transferase (GST) fusion protein in Escherichia coli. The GST-Bax fusion protein was bound to glutathione-Sepharose, and Bax was released by thrombin cleavage and further purified by sequential chromatography on heparin-Sepharose and DEAE-Sepharose. The purified protein was present in solution as a heptamer and multimers of the heptamer complex. Limited tryptic digestion cleaved the protein in the region preceding the BH3 domain and produced a specific stable protein fragment of 15 kDa. Phosphorylation has been proposed as a possible regulatory mechanism of the bcl-2 proteins. The Bax protein was an in vitro substrate for specific serine/threonine protein kinases.
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PMID:Purification and biochemical properties of soluble recombinant human Bax. 963 24

Previous studies have shown that glucose deprivation-induced cell death is associated with apoptosis, which is characterized by cellular membrane blebbing in multi-drug-resistant human breast carcinoma MCF-7/ADR cells. In this study, we investigated the mechanism of glucose deprivation-induced cytoskeletal reorganization, which is known to be responsible for the morphological alterations. An increase in the formation of focal adhesion and stress fibers was observed during the early period of glucose deprivation (1-2 h). However, a disappearance of focal adhesion complexes and a loss of stress fiber formation along with membrane blebbing were observed when glucose deprivation continued. These alterations were delayed in MCF-7/ADR cells transfected with bcl-2 and completely suppressed by treatment with an antioxidant, N-acetyl-L-cysteine. These results indicated that glucose deprivation-induced oxidative stress caused the cytoskeletal reorganization. The glucose deprivation-induced alteration of cytoskeletal organization was further investigated by studying a modification of paxillin, one of the focal adhesion proteins. Immunoblotting with anti-paxillin antibody showed that the paxillin band shifted from 68 kDa to about 80 kDa during 1-4 h of glucose deprivation. The mobility shift indicated the modification of paxillin. This possibility was further studied by an immunoprecipitation assay with anti-paxillin/anti-phosphotyrosine antibody and phosphoamino acid analysis (PAA). The immunoprecipitation study revealed that the level of tyrosine phosphorylation of paxillin was maintained for 2 h and then markedly decreased without a change in the total level of paxillin. The PAA study showed that paxillin is dephosphorylated on tyrosine concurrent with phosphorylation on serine/threonine. Expression of a dominant-negative mutant of c-Jun NH(2)-terminal kinase (JNK1) suppressed glucose deprivation-induced JNK1 activation, PTP-PEST gene expression, and alteration of paxillin. Taken together, these results suggest that the alteration of the phosphorylation/dephosphorylation of paxillin may be related to the cytoskeletal reorganization and these events are mediated by glucose deprivation-induced oxidative stress and the stress-activated protein kinase signal transduction pathway.
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PMID:Role of paxillin in metabolic oxidative stress-induced cytoskeletal reorganization: involvement of SAPK signal transduction pathway and PTP-PEST gene expression. 1096 6

The purpose of this study was to investigate the possible molecular mechanisms of the antiproliferative effect induced by protocatechualdehyde (PA, a dihydroxybenzene derivative). The viability of cytotoxic T cells (CfLL-2) stimulated by IL2 was significantly inhibited at 0.12 mM PA. This inhibitory effect was associated with the induction of apoptosis detected by DNA fragmentation assay. DNA ladder appeared at 0.12 mM PA and the intensity of DNA ladder was visible at 0.3 mM PA. PA inhibited the Ib2-dependent tyrosine phosphorylation of 91, 80 and 55 KDa proteins, but did not affect IL2-dependent serine/threonine phosphorylation of proteins. The levels of bcl-2 protein and mRNA were suppressed by PA. An alteration in bax protein expression on the apoptosis process in CTLL-2 cells was not observed. However, caspase-3 activity was increased by PA. Our results demonstrate that PA inhibited cell proliferation and induced apoptosis in CTLL-2 cells. It is concluded that PA is a potent anti-proliferative agent and is expected to be a promising candidate for novel therapeutics.
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PMID:Induction of apoptosis in CTLL-2 cells by protocatechualdehyde. 1139 45

Rapamycin, a specific inhibitor of the serine/threonine mTOR kinase, markedly inhibited both cell growth and apoptosis in human B-cell lines. Besides arresting cells in G(1) by increasing p27(kip1), rapamycin tripled the cellular level of the BCL-2 protein. The activity was dose-dependent and specific for the p27(kip1) and BCL-2 proteins. Rapamycin did not affect bcl-2 mRNA although it increased cellular BCL-2 concentration by inhibiting phosphorylation, a mechanism initiating the decay process. To add new insight, we combined rapamycin treatment with treatment by taxol, which, by damaging microtubules, can phosphorylate BCL-2 and activate apoptosis. It was found that the mTOR kinase was activated in cells treated with taxol or with nocodazole although it was inhibited in cells pre-treated with rapamycin. BCL-2 phosphorylation, apoptosis and hyperdiploidy were also inhibited by rapamycin. In contrast, taxol-induced microtubule stabilization or metaphase synchronization were not inhibited by rapamycin. Taken together, these findings indicate that mTOR belongs to the enzymatic cascade that, starting from damaged microtubules, phosphorylates BCL-2. By regulating apoptosis, in addition to the control of a multitude of growth-related pathways, mTOR plays a nodal role in signaling G(1) and G(2)-M events.
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PMID:Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase. 1159 25

The cribriform-morular variant (C-MV), an unusual and peculiar subtype of papillary thyroid carcinoma (PTC), has been observed frequently in familial adenomatous polyposis (FAP)-associated thyroid carcinoma and also in sporadic thyroid carcinoma. In this paper, five young women with the C-MV of PTC, aged 22-34 years at cancer diagnosis, are reported; two of them had attenuated FAP. Grossly, one FAP-associated tumour and one sporadic tumour were multicentric and the others were solitary. Histologically, the tumours were encapsulated and exhibited a combination of cribriform, follicular, trabecular, solid, and papillary patterns of growth, with morular areas. Immunohistochemically, the tumour cells showed cytoplasmic expression of thyroglobulin, neuron-specific enolase, epithelial membrane antigen, high- and low-molecular-weight cytokeratins, vimentin, and bcl-2 protein; nuclear expression of oestrogen and progesterone receptors, and retinoblastoma protein; and cytoplasmic and nuclear accumulation of beta-catenin. Germline mutations of the adenomatous polyposis coli (APC) gene were investigated using the protein truncation test in four subjects, including two FAP individuals. Germline APC mutation was identified in only one FAP patient with the multicentric C-MV of PTC, who had a thymidine deletion at codon 512, resulting in a frameshift leading to a premature stop codon. No loss of heterozygosity of loci close to the APC gene was detected in tumour tissues from these four patients. Somatic mutation analysis of exon 3 of the beta-catenin gene (CTNNB1) revealed alterations in seven tumours from all five individuals: one at a serine residue (codon 29), three at amino acids adjacent to serine or threonine residues (codons 22, 39, and 44), and three at other amino acids (codons 49, 54, and 56). Moreover, each of two different tumours examined from two patients with the multicentric C-MV of PTC, had different somatic mutations of the CTNNB1 gene. Taken together, these data suggest that accumulation of mutant beta-catenin contributes to the development of the C-MV of PTC.
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PMID:Cribriform-morular variant of papillary thyroid carcinoma: a pathological and molecular genetic study with evidence of frequent somatic mutations in exon 3 of the beta-catenin gene. 1247 27


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