Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to analyze the pathways regulating the expression of CD21 and CD23 B-cell differentiation antigens on human malignant B cells. Exposure of Farage cells, derived from a human B-cell lymphoma, to phorbol 12-myristate 13-acetate (PMA) down-regulated CD21 and CD23 expression, while interleukin 4 (IL4) inhibited the expression of CD21 but augmented CD23 expression. When Farage cells were stained with either anti-CD21 or anti-CD23 monoclonal antibodies (mAb), subsequent exposure to IL4 failed to change the staining of the cells, indicating that IL4 did not affect the turnover of CD21 and CD23 molecules. Inhibition of protein synthesis with cycloheximide (CXM) had no effect on the expression of CD21 molecules, but abrogated their down-regulation by IL4, suggesting that IL4 induced the synthesis of proteins which modify the processing of CD21 molecules. The inhibitory effect of IL4 on the expression of CD21 and its augmentary effect on the expression of CD23 was abrogated by H7 (1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine), an inhibitor of serine protein kinase. Staurosporine, an additional inhibitor of serine kinases also abrogated the effect of IL4 on CD23 expression. H8 (N-(2-[Methylamino]ethyl)-5-isoquinolinesulfonamide), a preferential inhibitor of protein kinases A and G, and genistein, an inhibitor of tyrosine kinases had no effect on IL4-induced modulation of CD21 and CD23 in Farage cells. The exposure of B-chronic lymphocytic leukemia (CLL) cells to PMA reduced the expression of CD21, but increased the expression of CD23. IL4 had no effect on the expression of CD21 on CLL-cells but strongly enhanced the level of CD23. H7, H8 and genistein each abrogated to a different extent the effect of IL4 on the expression of CD23 by CLL-cells. These data indicate that activation of serine/threonine kinases in malignant B cells inhibited the production of CD21 proteins, while different protein kinases appeared to be involved in up- and down-regulation of CD23 in different B lymphocytes.
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PMID:Pathways controlling the expression of surface CD21 (CR2) and CD23 (Fc(epsilon)IIR) proteins in human malignant B cells. 925 Aug 23

Using a random combinatorial synthetic peptide library method based on a one-bead one-peptide concept for ligand identification (Lam et. al, Nature 1991, 354, 82-84.), idiotype specific peptides were retrieved and optimized for interaction with the cell surface immunoglobulins [IgM(kappa)] of two murine B lymphoma cell lines. Several of the identified peptides were characterized with respect to cell binding and signal transduction. These peptides were able to bind specifically to the surface immunoglobulins of these lymphoma cells. In addition to binding, when synthesized in tetrameric or multimeric forms, the peptides were able to trigger signal transduction resulting in an increase in protein tyrosine phosphorylation. Since D-amino acid peptide libraries were used in some of our efforts to identify binding ligands, several of the idiotype-specific peptides are composed of all D-amino acids (e.g. wGeyvmvnG). These findings may have important therapeutic implications for targeted-therapy of B-cell lymphoma as these D-amino acid ligands are more resistant to proteolysis resulting in a prolonged pharmacokinetic disposition in vivo.
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PMID:Idiotype specific peptides bind to the surface immunoglobulins of two murine B-cell lymphoma lines, inducing signal transduction. 934 54

The 120 kD product of the c-Cbl oncogene is a prominent substrate of protein tyrosine kinases that lacks a known catalytic activity but possesses an array of binding sites for cytoplasmic signalling proteins. An oncogenic form of Cbl was recently identified in the 70Z/3 pre-B cell lymphoma which has a small deletion at the N-terminus of the Ring finger domain. This form of Cbl, termed 70Z-Cbl, exhibits an enhanced level of tyrosine phosphorylation compared with c-Cbl. Here we demonstrate that the expression of 70Z-Cbl induces a tenfold enhancement in the kinase activity of the EGF receptor in serum-starved and EGF-stimulated cells. In serum-starved cells this results in EGF receptor autophosphorylation and the recruitment of Grb2, Shc and Sos1 but does not induce a corresponding increase in MAP kinase activity. Furthermore the expression of 70Z-Cbl greatly enhances EGF-induced tyrosine phosphorylation of the protein tyrosine phosphatase SHP-2. We also show that the Cbl/EGF receptor complex is predominantly associated with CrkII and is distinct to the Grb2/Shc/Sos1 complex that associates with the EGF receptor. These findings therefore demonstrate a biochemical effect of an oncogenic Cbl protein and support predictions from C. elegans that Cbl functions as regulator of receptor tyrosine kinases.
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PMID:Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl. 941 34

BKS-2 is an immature B cell lymphoma that undergoes apoptotic cell death when signaled via its surface IgM receptor. To study the signaling components of surface IgM mediated apoptosis in B lymphoma cells, we generated mutants of BKS-2 that were resistant to anti-IgM induced apoptosis. One mutant cell line, 1.B5, did not undergo apoptotic cell death upon treatment with anti-IgM antibodies and also did not exhibit elevation of intracellular Ca2+ in response to cross-linking of surface IgM. This appeared to be due to a defect in protein tyrosine kinase (PTK) activity since fewer proteins were tyrosine phosphorylated in the mutant cells stimulated with anti-IgM when compared to wild type BKS-2. Subsequently, we showed that protein tyrosine kinases lyn and blk were inducibly tyrosine phosphorylated in the wild type BKS-2 but not in 1.B5 mutant cells in response to anti-IgM. Also the kinase activity of lyn was elevated in the wild type but not in mutant cells upon triggering through surface IgM. Furthermore, tyrosine phosphorylation of CD19, a known substrate of lyn, was inducible in anti-IgM stimulated BKS-2 cells but severely reduced in 1.B5 cells. In contrast, kinase activity of another src kinase, blk, was increased on anti-IgM stimulation in both wild type and mutant cells. Surprisingly, syk, a non-src protein tyrosine kinase important for surface IgM mediated signaling, was tyrosine phosphorylated in the lyn deficient mutant cells as well as in the wild type BKS-2 cells. Furthermore, anti-IgM induced increase in kinase activity of syk was similar in the mutant and wild type cells. Thus, in contrast to other studies that propose syk to be a downstream target of src family kinases, syk may act upstream of lyn in immature B cells. Consistent with a functional syk, its target, phospholipase gamma2 (PLC-gamma2) was normally tyrosine phosphorylated in mutant cells.
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PMID:Activation of syk in an immature B cell line does not require lyn activity. 946 22

The ability of ionic mercury to induce protein tyrosine phosphorylation in mouse spleen cells and in the mouse WEHI-231 B-cell lymphoma was investigated. We have confirmed previous studies which showed that exposure to high levels (several hundred microM) of mercury lead to very large increases in the level of protein tyrosine phosphorylation in these cell systems. However we have also demonstrated that low levels (in the order of 0.1 to 1.0 microM) of mercury also significantly upregulate protein tyrosine phosphorylation. Mercury induced protein tyrosine phosphorylation is inhibited by the mercury chelator penicillamine and by pretreating treating target cells with the sulfhydryl blocking reagent N-hydroxymaleimide. These results suggest that exposure to low levels of mercury could potentially interfere with lymphocyte signal transduction and so offer a possible explanation as to how mercury exposure could lead to immune cellular dysfunction. On a molecular level, the results suggest that the site(s) of action with respect to mercury dependent induction of protein tyrosine phosphorylation is likely a free disulfide group or groups located on the outer leaflet of the plasma membrane.
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PMID:Low levels of ionic mercury modulate protein tyrosine phosphorylation in lymphocytes. 987 81

The Src-homology domain 2 (SH2)-containing cytoplasmic tyrosine phosphatase, SHP-1 (SH2-containing protein tyrosine phosphatase-1), interacts with several B cell surface and intracellular signal transduction molecules through its SH2 domains. Mice with the motheaten and viable motheaten mutations are deficient in SHP-1 and lack most mature B cells. To define the role of SHP-1 in mature B cells, we expressed phosphatase-inactive SHP-1 (C453S) in a mature B cell lymphoma line. SHP-1 (C453S) retains the ability to bind to both substrates and appropriate tyrosine-phosphorylated proteins and therefore can compete with the endogenous wild-type enzyme. We found that B cells expressing SHP-1 (C453S) demonstrated enhanced and prolonged tyrosine phosphorylation of proteins with molecular masses of 110, 70, and 55-60 kDa after stimulation with anti-mouse IgG. The tyrosine kinase Syk was hyperphosphorylated and hyperactive in B cells expressing SHP-1 (C453S). SHP-1 and Syk were coimmunoprecipitated from wild-type K46 cells, K46 SHP-1 (C453S) cells, and splenic B cells, and SHP-1 dephosphorylated Syk. Cells expressing SHP-1 (C453S) showed increased Ca2+ mobilization, extracellular signal-regulated kinase activation, and homotypic adhesion after B cell Ag receptor engagement. Thus, SHP-1 regulates multiple early and late events in B lymphocyte activation.
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PMID:Expression of dominant-negative src-homology domain 2-containing protein tyrosine phosphatase-1 results in increased Syk tyrosine kinase activity and B cell activation. 1007 16

The optimal use of radioiodinated internalizing monoclonal antibodies (mAbs) for radioimmunotherapy necessitates the development of practical methods for increasing the level of retention of 131I in the tumor. Lysosomally trapped ("residualizing") iodine radiolabels that have been previously designed are based mostly on carbohydrate-tyramine adducts, but these methods have drawbacks of low overall yields and/or high levels of mAb aggregation. We have developed a method using thiol-reactive diethylenetriaminepentaacetic acid (DTPA)-peptide adducts wherein the peptides are assembled with one or more D-amino acids, including D-tyrosine. Two such substrates, R-Gly-D-Tyr-D-Lys[1-(p-thiocarbonylaminobenzyl)DTPA], referred to as IMP-R1, and [R-D-Ala-D-Tyr-D-Tyr-D-Lys]2(CA-DTPA), referred to as IMP-R2, wherein R is 4-(N-maleimidomethyl)cyclohexane-1-carbonyl, were synthesized by preparing functional group-protected peptides on a solid phase, selectively derivatizing the lysine side chain with 1-(p-isothiocyanatobenzyl)DTPA or DTPA dianhydride (CA-DTPA), deprotecting other functional groups, and finally derivatizing the peptide's N-terminus so it contained a maleimide group. Radioiodinations of the peptides followed by conjugations to disulfide-reduced mAbs, carried out as a one-vial procedure, resulted in 32-89% overall yields, at specific activities of 1.8-11. 1 mCi/mg, with less than 2% aggregation. Two internalizing mAbs, LL2 (anti-CD 22 B-cell lymphoma mAb) and RS7 (an anti-adenocarcinoma mAb which targets EGP-1 antigen), labeled with this procedure exhibited a 2-3-fold better cellular retention in Ramos and Calu-3 tumor cell lines, in vitro, respectively, compared to the same mAbs radioiodinated with the chloramine-T method. The rationale for the new approach, syntheses, radiochemistry and in vitro data are presented.
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PMID:Labeling of monoclonal antibodies with diethylenetriaminepentaacetic acid-appended radioiodinated peptides containing D-amino acids. 1007 72

During an ongoing immune response, immune complexes, composed of Ag, complement factors, and Igs, are formed that can interact with complement receptors (CRs) and IgG Fc receptors (Fc gamma R). The role of CR1/2 and Fc gamma R in the regulation of the immune response was investigated using OVA that was chemically conjugated to whole IgG of the rat anti-mouse CR1/2 mAb 7G6. FACS analysis using the murine B cell lymphoma IIA1.6 confirmed that the 7G6-OVA conjugate recognized CR1/2. Incubating IIA1.6 cells with 7G6-OVA triggered tyrosine phosphorylation and Ag presentation to OVA-specific T cells in vitro. Immunizing mice with 7G6-OVA at a minimal dose of 1 microgram i.p. per mouse markedly enhanced the anti-OVA Ig response, which was primarily of the IgG1 isotype subclass. The 7G6-OVA did not enhance the anti-OVA response in CR1/2-deficient mice. OVA coupled to an isotype control Ab induced a considerably lower anti-OVA response compared with that induced by OVA alone, suggesting inhibition by interaction between the Fc part of the Ab and the inhibitory Fc gamma RIIb on B cells. This findings was supported by the observation that IIA1.6 cells which were incubated with 7G6-OVA lost the ability to present Ag upon transfection with Fc gamma RIIb. In sum, 7G6-conjugated OVA, resembling a natural immune complex, induces an enhanced anti-OVA immune response that involves at least CR1/2-mediated stimulation and that may be partially suppressed by Fc gamma RIIb.
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PMID:Modulation of the humoral immune response by antibody-mediated antigen targeting to complement receptors and Fc receptors. 1009 61

Tyrosine kinases causing the abnormal phosphorylation of intracellular proteins have been shown to contribute to oncogenic transformation in a number of human neoplasms. Immunohistological staining of routine biopsy sections for increased levels of phosphotyrosine may therefore provide a simple means of screening for tumours containing activated tyrosine kinases. In this study, monoclonal antibodies to phosphotyrosine were used to immunostain a cell line and tumour biopsies from lymphomas known to contain the activated anaplastic-lymphoma-kinase (ALK) tyrosine kinase. A range of normal and other neoplastic tissues were also immunostained for comparison. An anaplastic large cell lymphoma (ALCL) cell line carrying the (2;5) translocation, which creates the activated nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase, was strongly labelled. Routine tissue biopsies from five cases of ALK-positive ALCL were also strongly positive for phosphotyrosine. The characteristic granular cytoplasmic labelling pattern for phosphotyrosine observed in a B-cell lymphoma (expressing full length ALK kinase) was identical to that obtained using an ALK-specific antibody, thus confirming that labelling for phosphotyrosine in lymphoma cells reflects the presence of an activated kinase. When normal lymphoid tissues were stained, there was little or no labelling for phosphotyrosine, but stronger labelling was seen in other cells and tissues; for example, endothelial cells and some carcinoma samples. Whilst the strong labelling for phosphotyrosine observed in the lymphoma cells is due to the presence of activated ALK, the strong staining of some normal cells presumably represents physiologically active kinases and this should be taken into account when interpreting the immunostaining of non-lymphoid tumours. The simplicity of this method, however, means that it offers a new rapid approach to the screening of large numbers of tumours for the presence of aberrant tyrosine kinase activation, particularly if they arise from tissues which normally contain only background levels of phosphotyrosine.
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PMID:Immunohistochemical screening for oncogenic tyrosine kinase activation. 1039 26

Western blots using an antibody which recognizes the orphanin FQ/nociceptin (OFQ/N) receptor reveals a band at approximately 69 kD in several cell lines, including the Raji human B cell lymphoma cell line. RT-PCR confirms the presence of this receptor in the Raji cells. Binding studies revealed a high affinity [(125)I][Tyr(14)]OFQ/N site in the Raji cells. The affinity of [(125)I][Tyr(14)]OFQ/N in the Raji cells (K(D) 68.4 pM) was similar to that in the transfected receptor (K(D) 36.7 pM). Its selectivity profile also was quite similar. OFQ/N competed binding quite potently (K(i) 65 pM), as did [Tyr(14)]OFQ/N (K(i) 33 pM). Traditional opioids displayed no appreciable affinity for the binding at any concentration examined, with the exception of naloxone benzoylhydrazone, which had only a very modest affinity. The receptors in the Raji cells were functionally active. OFQ/N inhibited forskolin-stimulated cyclase by 72% with an IC(50) value of approximately 1 nM.
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PMID:[(125)I]orphanin FQ/nociceptin binding in Raji cells. 1052 56


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