Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Engagement of the cell surface receptor for interleukin 7 (IL-7R) provokes protein tyrosine phosphorylation, although the receptor lacks a kinase catalytic domain in its cytoplasmic tail. The molecular basis of this response is not known. Here we report that the IL-7R functions by recruiting p59fyn, an intracellular tyrosine kinase of the src family. Treatment of pre-B cells with IL-7 causes an enhancement of the catalytic activity of p59fyn, but not of the related kinase p62yes. IL-7-dependent stimulation of the enzyme phosphatidylinositol 3-kinase, a tyrosine kinase substrate, provides further evidence suggestive of p59fyn activation. We demonstrate that p59fyn forms part of a protein complex with the IL-7R. A chimeric receptor comprising the CD8 extracellular domain and the IL-7R cytoplasmic tail (CD8/IL-7R) recruits tyrosine kinase activity in transfected myeloma cells, and p59fyn can be detected in association with it by immunoprecipitation and immunoblotting. Conversely, p59fyn immunoprecipitates contain the phosphorylated CD8/IL-7R. We have identified a segment of the IL-7R cytoplasmic tail which mediates p59fyn recruitment: a truncated CD8/IL-7R containing only this segment recruits tyrosine kinase activity, associates with p59fyn, and activates phosphatidylinositol 3-kinase. Interestingly, this segment contains no tyrosine residues, although it is the phosphotyrosine-binding src homology domains of p59fyn and phosphatidylinositol 3-kinase which mediate their association with many growth factor receptors. Thus our results suggest that an unusual interaction links IL-7R to these two important signaling pathways.
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PMID:Interleukin 7 receptor functions by recruiting the tyrosine kinase p59fyn through a segment of its cytoplasmic tail. 146 44

Soluble interleukin-6 receptor (sIL-6R) was found to be spontaneously released from human myeloma cell line U266 cells into culture supernatant, and was quantitatively measured with a fluorescence sandwich enzyme-linked immunosorbent assay employing antibodies specific to IL-6R. The supernatant IL-6R was generated only from IL-6R-positive cell lines; myeloma cell lines RPMI8226 and PRMI1788, and myelomonocytic cell lines U937, THP-1, and HL-60. In contrast, it was not released from the IL-6R-negative cells; T cell line Molt-4 and Burkitt lymphoma cell line Raji. SDS-PAGE analysis of the soluble IL-6R from U266 cells suggested a molecular weight of approximately 50-55 kDa, 25-30 kDa smaller than the mature cell surface receptor. These results suggest that the generation of soluble IL-6R may be a maker of myeloma cells and myelomonocytic cells.
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PMID:Soluble interleukin-6 receptor is released from receptor-bearing cell lines in vitro. 150 71

Three efficient mouse interferon gamma (MoIFN gamma) inhibitors were constructed, which consist of the MoIFN gamma receptor (MoIFN gamma R) extracellular portion and constant domains of immunoglobulin (Ig) molecules. These are: 1) the constant domain of the mouse kappa chain, 2) the hinge region and the constant domains 2 and 3 of the mouse gamma 2a chain, and 3) the hinge region and the constant domains 2 and 3 of the human gamma 3 chain. The hybrid molecules were expressed in the mouse myeloma cell line J558L and recovered from the supernatants of cell cultures in one purification step. The proteins MoIFN gamma R-M gamma 2a and MoIFN gamma R-H gamma 3 form homodimers, whereas MoIFN gamma R-M kappa is a monomer. All three constructs inhibit the binding of radiolabeled MoIFN gamma to its receptor on L1210 cells. They are biologically active in vitro, neutralizing the action of MoIFN gamma in an antiviral activity assay. The fusions of Ig regions to the soluble MoIFN gamma R do not decrease the affinity of the binding site for the ligand. MoIFN gamma R-M kappa has about the same affinity as the soluble MoIFN gamma R and the cell surface receptor of L1210 cells in situ, which are also monomers, whereas the dimers MoIFN gamma R-M gamma 2a and MoIFN gamma R-H gamma 3 display a 5-10-fold higher affinity for MoIFN gamma than the monomeric molecules. This is best documented in the efficacy of the inhibitors to antagonize the antiviral activity of MoIFN gamma, as the dimeric constructs are about 10 times more active than MoIFN gamma R-M kappa and the soluble MoIFN gamma R. The hybrid constructs can be used as high efficiency MoIFN gamma inhibitors in mouse models of several pathological states in humans, where IFN gamma is thought to play a disease-promoting role.
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PMID:Construction, purification, and characterization of new interferon gamma (IFN gamma) inhibitor proteins. Three IFN gamma receptor-immunoglobulin hybrid molecules. 153 30

To identify Fc epsilon receptors on human cell lines and peripheral blood lymphocytes, we developed a new method which relies on the binding of constructed immune complexes to Fc epsilon receptor-positive cells. Cell suspensions from either cell lines or peripheral blood lymphocytes were incubated with complexes of human myeloma IgE and murine monoclonal anti-human IgE at various ratios prior to cytocentrifugation. The complexes bound to the cells were subsequently visualized by immunoperoxidase staining. The specificity of this assay to detect cell surface Fc epsilon receptors was shown by the ability of human myeloma IgE to block the binding of the IgE complexes, resulting in unstained cells, whereas IgM, IgG, and IgA were unable to block the binding of the complexes (stained cells). This method is reproducible, allows quantification of a single sample at different times, and provides a record of the results. It can also be adapted to identify any cell surface receptor for which the ligand is known.
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PMID:Fc epsilon receptors on human cell lines and peripheral blood lymphocytes detected by binding of IgE immune complexes. 315 72

T cell-replacing factor (TRF)/IL-5 is a glycosylated polypeptide that acts as a key factor for B cell growth and differentiation. Since IL-5 action is probably mediated by specific cell surface receptor(s), we have characterized the binding of IL-5 to cells using biosynthetically [35S]methionine-labeled IL-5 and 125I-IL-5 that had been prepared using Bolton-Hunter reagent. The radiolabeled IL-5 binds specifically to BCL1-B20 (in vitro line) (a murine chronic B cell leukemic cell line previously shown to differentiate into IgM-secreting cells in response to IL-5) within 10 min at 37 degrees C. There are two classes of binding sites with high affinity (Kd = 66 pM) and low affinity (Kd = 12 nM) for IL-5 and an average number of binding sites for high affinity and for low affinity were 400 and 7,500 per cell, respectively. The specificity of binding of radiolabeled IL-5 has been confirmed by demonstrating that only unlabeled IL-5 and anti-IL-5 mAb but not by IL-1, IL-2, IL-3, IFN-gamma, and GM-CSF inhibit radiolabeled IL-5 binding to BCL1-B20 cells. Treatment of surface-bound radiolabeled IL-5 with bivalent crosslinkers identified a membrane polypeptide of Mr 46,500 to which IL-5 is crosslinked. A variety of cell types have been surveyed for the capacity to bind specifically radiolabeled IL-5 with high affinity. BCL1 cells MOPC104E (murine myeloma cell line) expressed IL-5-R, whereas BAL. 17 and L10 A (B cell lymphoma) did not. T cell line, mastocytoma cell line, or macrophage tumor cell line did not display detectable levels of IL-5-R. were hardly detectable on normal resting B cells but were expressed on LPS-activated B cells, fitting the function of IL-5 that acts on activated B cells for their differentiation into Ig-secreting cells. Intriguingly, early B cell lines (J-87 and T-88) that grow in the presence of IL-5 expressed significant but low numbers of high-affinity binding sites for IL-5. The biological effects of IL-5 were mediated by high-affinity binding sites. The identification and characterization of IL-5-R should provide new insight into the apparent diverse biological activities of IL-5.
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PMID:Receptors for T cell-replacing factor/interleukin 5. Specificity, quantitation, and its implication. 326 7

Herpes simplex virus is known to induce an immunoglobulin-binding cell surface receptor in infected cells that utilizes a nonimmune mechanism. In the present paper, we report the immunoglobulin class and subclass specificity of this receptor. Of the human immunoglobulins G(IgG), IgA, IgM, and IgD, as well as the structurally related beta2 microglobulin, only IgG and its Fc portion exhibited an increased binding to herpes simplex virus-infected cells versus uninfected control cells. The IgG subclass specificity of the Fc receptor was studied in 37 radioiodinated IgG myeloma proteins representing all four subclasses. We found that IgG3 myeloma proteins did not bind to herpes simplex virus-infected cells to a greater extent than to uninfected cells. On the contrary, proteins belonging to the other subclasses exhibited an increased binding to herpes simplex virus-infected cells of the following relative magnitude: IgG4 greater than IgG1 greater than or equal to IgG2. This increment of binding could be abolished by addition of a large excess of human IgG Fc fragment. Evidence for the existence of a variable herpes simplex virus-specific binding ability between myeloma proteins belonging to the same IgG subclass was also obtained. Furthermore, we tested two other herpes simplex virus type 1 strains with a limited number of myeloma proteins with very similar results as with the herpes simplex virus type 1 F strain. Several sources of experimental artefacts were controlled, including the state of aggregation of the test proteins, the functional integrity of the Fc portion before and after radioiodination, and the subclass assignments. The implications for the biological role of the Fc receptor of herpes simplex virus are discussed.
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PMID:Human immunoglobulin class and subclass specificity of Fc receptors induced by herpes simplex virus type 1. 632 9

Stable cloned lines of anti-B-secreting cells have been derived by fusing spleen cells of a mouse immunized by group B antigen with a mouse myeloma line. The tissue culture supernatant of one of them (NB1/19.112.28) containing secreted monoclonal anti-B antibody is an especially good blood-grouping reagent, well suited for use with manual and automated methods. The unlimited availability of a potent reagent of uniform properties, cheaply produced by a single source, makes monoclonal anti-B a serious competitor to human typing serum.
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PMID:Monoclonal anti-B as a new blood-typing reagent. 678 27

The vav proto-oncogene product (p95vav) is specifically expressed in cells of the hematopoietic system, contains one Src homology 2 and two Src homology 3 domains, and is a substrate for receptor and non-receptor tyrosine kinases. Immunoblotting experiments using an anti-phosphotyrosine monoclonal antibody showed that interferon alpha (IFN alpha) induces rapid tyrosine phosphorylation of p95vav after binding to its cell surface receptor in the U-266 human myeloma cell line. The IFN alpha-induced tyrosine phosphorylation of p95vav was time- and dose-dependent, confirming the specificity of the process. IFN alpha-dependent tyrosine phosphorylation of p95vav was also observed in other hematopoietic cell lines of B-cell origin (Daudi), T-cell origin (MOLT-4), and promyelocytic origin (HL-60). Immunoprecipitation experiments performed with 32P-labeled U-266 cells and phosphoaminoacid analysis of the bands corresponding to p95vav showed that p95vav is phosphorylated on serine residues prior to IFN alpha stimulation of the cells. After IFN alpha stimulation significant amounts of phosphorylation of p95vav on tyrosine residues were detectable. Tyrosine phosphorylation of p95vav in U-266 and HL-60 cells was also induced by two other Type I IFNs, IFN beta and IFN omega. Altogether these data suggest that the vav proto-oncogene product is a substrate for a Type I IFN-regulated tyrosine kinase(s) and may be involved in the signal transduction pathway of Type I IFNs in hematopoietic cells.
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PMID:Interferon alpha induces rapid tyrosine phosphorylation of the vav proto-oncogene product in hematopoietic cells. 750 9

We have previously reported that polymorphonuclear granulocyte (PMN) and monocyte oxidative metabolism is reduced in polycythemia vera (PV) patients compared to healthy control subjects, after stimulation with cell surface receptor-dependent stimuli such as n-formyl-methionyl-leucyl-phenylalanine, leukotriene B4 and platelet-activating factor (PAF). In contrast, the oxidative response to phorbol myristate acetate (PMA) is normal. We now show that, in PV patients exhibiting significantly reduced PMN chemiluminescence after PAF stimulation, PAF induced platelet aggregation was also reduced--40 +/- 3% compared to 50 +/- 2% in controls (p < 0.01). The defective aggregatory response to PAF in PV remained over a wide range of stimuli concentrations. Platelet aggregation induced by PMA and ADP, however, was similar in PV and controls. In contrast, platelet aggregation induced by PAF (or by ADP and PMA) was not significantly reduced in patients with chronic myeloid leukemia, essential thrombocythemia and multiple myeloma. Furthermore, the release of beta-thromboglobulin was slightly but not significantly higher after PAF stimulation in PV and this argues against an abnormal PAF receptor as the cause of the defective function. Thus, not only PV neutrophils, but also PV platelets show a discrete defect of the stimulus response coupling for PAF, indicating a disease-specific abnormality that appears to be of clonal origin.
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PMID:Stimulus-specific defect in platelet aggregation in polycythemia vera. 792 57

Multiple myeloma (MM) is a plasma-cell malignancy characterized by the accumulation of malignant plasma cells within the bone marrow. Interleukin (IL)-6 is an essential survival and growth factor for myeloma cells that exerts its activity through a cell surface receptor composed of an 80-kDa ligand binding molecule (IL-6Ralpha) and a 130-kDa signal-transducing molecule. Of major interest, the soluble form of the IL-6Ralpha (sIL-6Ralpha) is an agonistic molecule able to potentiate IL-6 activity and a strong prognostic factor in MM. In the present study, we demonstrate that purified myeloma cells from all of the patients with MM and human myeloma cell lines release sIL-6Ralpha. The level of sIL-6Ralpha release correlates with disease activity and is clearly up-regulated during tumoral expansion in vivo and immortalization in vitro. Of note, this sIL-6Ralpha release is strongly reduced (50%) by a hydroxamate-based metalloproteinase inhibitor underlying the importance of shedding in the production of sIL-6Ralpha by myeloma cells. Using specific IL-6Ralpha primers flanking the transmembrane domain, we demonstrate by PCR the presence of two IL-6R mRNAs corresponding to the membrane IL-6Ralpha and to the sIL-6Ralpha generated through alternative splicing in myeloma cells. In conclusion, we show that: (a) native myeloma cells and human myeloma cell lines release sIL-6Ralpha by two distinct mechanisms: alternative splicing and proteolytic cleavage of the membrane IL-6Ralpha; and (b) the release of the sIL-6Ralpha, which is an agonist of IL-6, correlates with disease progression, explaining in part its strong prognostic value in vivo.
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PMID:Myeloma cells release soluble interleukin-6Ralpha in relation to disease progression by two distinct mechanisms: alternative splicing and proteolytic cleavage. 1053 31


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