Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Although the hairy cells (HCs) of hairy cell leukaemia (HCL) are now thought to be a form of activated B cell, they have long been known to possess certain monocytoid characteristics. Since the proto-oncogene c-fms is a feature of cells of the monocyte/macrophage lineage, we examined HCs for c-fms expression. We found that approximately 80% of peripheral blood HCs expressed the c-fms protein (8/8 cases). Expression of the 150 kD protein by HCs was shown using three different techniques, APAAP, immunofluorescence and immunoprecipitation, using two different antibodies. Other mature B cell lymphoproliferative disorders examined (PLL, CLL and multiple myeloma) did not express c-fms. We also examined the c-fms expression of normal B-cells: both the in vivo activated (low density) fraction of tonsil B cells and tonsil B cells activated in vitro with SAC plus IL-2 expressed the c-fms protein. As in the case of monocytes c-fms expression by HCs was shown to be down regulated by its ligand M-CSF, and by TNF alpha, both caused a decrease in the receptor expression from 80% to 30% and in the intensity of staining from 6 to 3 x 10(4) molecules/cell. However, as for monocytes, GM-CSF treatment of HCs had no effect on the expression of c-fms; alpha IFN also had no effect. M-CSF treatment of HCs also induced phosphorylation of c-fms, and a number of other proteins, on tyrosine. However, M-CSF was unable to induce HC proliferation either alone or in combination with IL-2, IL-4 or IL-6; in addition it had no effect on HC proliferation induced by SAC, anti-mu or TNF alpha. In addition, M-CSF either alone, or in combination with the above cytokines, had no effect on the differentiated state of HCs as shown by both immunoglobulin secretion and surface antigen expression. M-CSF also had no effect on the morphology or long-term survival of HCs in culture. This study therefore demonstrates that both HCs and activated B-cells express c-fms, and that M-CSF binds to and activates its receptor on HCs. Although c-fms and several other proteins were shown to be phosphorylated in response to M-CSF, the functional consequences of this phosphorylation remain unclear.
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PMID:C-fms protein expression by B-cells, with particular reference to the hairy cells of hairy-cell leukaemia. 830 20

Overexpression of the transmembrane protein-tyrosine phosphatase (PTPase) CD45 in nonhematopoietic cells results in decreased signaling through growth factor receptor tyrosine kinases. Consistent with these data, insulin receptor signaling is increased when the CD45-related PTPase LAR is reduced by antisense suppression in a rat hepatoma cell line. To test whether the hematopoietic cell-specific PTPase CD45 functions in a manner similar to LAR by negatively modulating insulin receptor signaling in hematopoietic cells, the insulin-responsive human multiple myeloma cell line U266 was isolated into two subpopulations that differed in CD45 expression. In CD45 nonexpressing (CD45-) cells, insulin receptor autophosphorylation was increased by 3-fold after insulin treatment when compared to CD45 expressing (CD45+) cells. This increase in receptor autophosphorylation was associated with similar increases in insulin-dependent tyrosine kinase activation. These receptor level effects were paralleled by postreceptor responses. Insulin-dependent tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and Shc was 3-fold greater in CD45- cells. In addition, insulin-dependent IRS-1/phosphatidylinositol 3-kinase association and MAP kinase activation in CD45- cells were also 3-fold larger. While expression of CD45 was associated with a decrease in the responsiveness of early insulin receptor signaling, interleukin 6-dependent activation of mitogen-activated protein kinase kinase and mitogen-activated protein kinase was equivalent between CD45- and CD45+ cells. These observations indicate that CD45 can function as a negative modulator of growth factor receptor tyrosine kinases in addition to its well-established role as an activator of src family tyrosine kinases.
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PMID:The transmembrane protein-tyrosine phosphatase CD45 is associated with decreased insulin receptor signaling. 855 83

The vav proto-oncogene product (p95(vav)) is specifically expressed in cells of hematopoietic origin and has one src homology 2 (SH2) domain, two SH3 domains, and motifs typical of guanine exchange factors. Insulin-like growth factor-1 (IGF-1) receptors are expressed on a variety of hematopoietic cells and, upon ligand binding, mediate signals regulating hematopoietic cell proliferation. We studied the phosphorylation status of p95(var) in the U-255 human myeloma cell line, in response to IGF-1 stimulation. Immunoblotting experiments with an antiphosphotyrosine monoclonal antibody disclosed that p95(vav) is phosphorylated on tyrosine in an IGF-1-dependent manner. The tyrosine phosphorylation of 95(vav was rapid, appearing within 5 minutes of IGF-1 treatment, amd transient, diminishing by 90 minutes. Similar results were obtained when the mouse plasmacytoma J558L cell line was studied. IGF-1-dependent tyrosine phosphorylation of p95(vav) was also seen in the 32D mouse myeloid cell line that lacks expression of insulin receptor substrate (IRS) proteins, suggesting that it is not regulated by activation of the IRS-signaling system. Taken together, these data suggest that the vav proto-oncogene is a substrate for the IGF-1 receptor tyrosine++ kinase and may be involved in the signal transduction of IGF-1 in cells of hematopoietic origin.
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PMID:Insulin-like growth factor-1 induces rapid tyrosine phosphorylation of the vav proto-oncogene product. 860 67

Like many other cytokines and growth factors, interleukin-6 (IL-6) activates p21ras. However, the precise biochemical mechanisms inducing this activation are unknown. Therefore, we investigated the effects of IL-6 on some recently identified signaling intermediates, Shc (Src homology and collagen) and Grb2 (growth factor receptor bound protein 2), known to activate p21ras. In the multiple myeloma cell line LP-1, IL-6 stimulated the tyrosine phosphorylation of Shc in a time- and concentration-dependent manner. This led to the complex formulation of Shc with Grb2, an adaptor protein known to relocate a p21ras-GDP exchange factor. Sos1 (Son-of-sevenless), to the cell membrane. Taken together, these findings suggest that IL-6 might activate the Ras signaling pathway via tyrosine phosphorylation of Shc and subsequent recruitment of Grb2. Further studies will elucidate which of the IL-6 receptor associated non-receptor tyrosine kinases of the Src kinase or Janus kinase family, mediate these effects.
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PMID:Interleukin-6 induces tyrosine phosphorylation of the Ras activating protein Shc, and its complex formation with Grb2 in the human multiple myeloma cell line LP-1. 861 7

Activation of early response genes by interferons (IFNs) requires tyrosine phosphorylation of the Stat transcription factors and is mediated by the Jak family of tyrosine kinases. Recent evidence suggests that ERK2 serine/threonine kinase modulates the IFN-stimulated Jak/Stat pathway. In this report we show that in the myeloma cell line U266 protein kinase A specifically interacts with the cytoplasmic domain of the IFNalpha/beta receptor. Treatment of cells with the adenylate cyclase activator forskolin inhibits IFNbeta-, IFNgamma-, and hydrogen peroxide/vanadate-induced formation of complexes that bind to enhancers known to stimulate the expression of IFN-regulated genes. Immunoprecipitations followed by anti-phosphotyrosine immunoblots indicate that tyrosine phosphorylation of the alpha chain of the IFNalpha/beta receptor, Jak1, Tyk2, as well as Stat1 and Stat2 is reduced as a consequence of incubation of cells with forskolin. In contrast, dideoxyforskolin, which fails to activate adenylate cyclase, has no effect on IFN induction of the Jak/Stat pathway. These results indicate a novel regulatory mechanism by which protein kinase A can modulate the Jak/Stat signaling cascade.
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PMID:Activation of protein kinase A inhibits interferon induction of the Jak/Stat pathway in U266 cells. 861 15

Pigpen is a 67-kDa Sepharose-binding molecule isolated from mammalian endothelial and retinal pigmented epithelial cells. The protein is distributed nonhomogeneously in the nucleus, exhibiting diffuse staining throughout (excluding nucleoli), together with a small number of intensely stained focal points, or granules, and punctate staining along the nuclear envelope. Pigpen was absent or greatly attenuated in the nonepithelial cell types we examined, including fibroblasts, myeloma, and astroglia. cDNA sequence analysis revealed a positively charged molecule with an RNP-CS RNA-binding domain, 19 RGG repeats, and a consensus tyrosine phosphorylation site in the C-terminus. The amino terminal portion of the molecule is characterized by 7 glutamine-rich hexapeptide repeats similar to those found in the transactivation domain of known transcription activators. Pigpen has a high level of identity with the FUS gene product, TLS (Translocated in Liposarcoma; Crozat et al, 1993; Rabbits et al., 1993), a new member of the EWS family of proteins. Expression of pigpen is regulated during the transition between active and quiescent endothelial cell phenotypes. Both mRNA and overall protein levels are maintained at a steady level in actively growing cells. The number of nuclear granules increases as cultures approach confluency. When cells reach confluency, overall expression is sharply reduced and the number of nuclear focal points declines gradually. We observed that reactivation of endothelial cells locally by wounding of confluent cultures resulted in a spatially restricted reactivation of pigpen expression. This pattern of expression, taken together with structural data, suggests that pigpen may function in the growth and differentiation of endothelial cells during angiogenesis.
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PMID:A nuclear protein regulated during the transition from active to quiescent phenotype in cultured endothelial cells. 863 1

Splenocytes from mice bearing a cachexia-inducing tumor (MAC16) have been fused with mouse myeloma cells to produce hybridomas, which have been cloned to produce antibody reactive to a material which copurified with a lipid-mobilizing factor isolated from the same tumor. The monoclonal antibody has been used to investigate factors potentially involved in the development of cachexia. The major protein detectable by immunoprecipitation of a partially purified lipid-mobilizing factor was M(r) 69,000, whereas Western blotting showed two bands of M(r) 69,000 and M(r) 24,000. Although the monoclonal antibody did not neutralize lipid-mobilizing activity in an in vitro assay, it did neutralize a serum factor capable of protein degradation in isolated gastrocnemius muscle. Affinity purification of MAC16 tumor homogenates using the monoclonal antibody yielded two immunoreactive bands of M(r) 69,000 and M(r) 24,000, which were further fractionated on a hydrophobic column (C8). This material was capable of inducing tyrosine release from isolated gastrocnemius muscle, and the effect could be blocked with the monoclonal antibody. The two immunoreactive bands from the hydrophobic column were capable of inducing weight loss in mice, whereas nonimmunoreactive fractions had no effect on body weight. The M(r) 24,000 species had a unique amino acid sequence, whereas the M(r) 69,000 species gave the same sequence as the M(r) 24,000 material, together with that for albumin. The M(r) 24,000 species contained carbohydrate, and lectin blotting showed a strong reaction with wheat germ and Erythrina crystagalli agglutinins. This suggests that the material is a glycoprotein or proteoglycan that shows strong binding affinity for albumin, possibly through the carbohydrate residues.
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PMID:Induction of muscle protein degradation and weight loss by a tumor product. 864 Aug 10

The c-cbl proto-oncogene product (p120cbl) forms a stable complex with the Tyk-2 protein tyrosine kinase in various human cell lines of diverse hematopoietic origin. In U-266 myeloma and 293T embryonic kidney cells, p120cbl is rapidly phosphorylated on tyrosine in an IFN alpha-dependent manner. p120cbl also acts as a specific substrate for the Tyk-2-associated SHP-1 phosphatase in vitro, suggesting that this phosphatase plays a regulatory role on the phosphorylation of the protein. These data provide evidence that p120cbl interacts with the functional Type I IFN receptor complex, and suggest its involvement in IFN alpha signaling.
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PMID:Interaction of the c-cbl proto-oncogene product with the Tyk-2 protein tyrosine kinase. 878 Jun 98

Type I interferons (IFNs-alpha and IFN-beta) bind to a common receptor to exert strong antiproliferative activity on a broad range of cell types, including interleukin-6 (IL-6)-dependent myeloma cells. In this study, we investigated the effect of IFN-beta pretreatment on IL-6-stimulated mitogenic signaling in the human myeloma cell line U266. IL-6 induced transient tyrosine phosphorylation of the IL-6-receptor signal-transducing subunit gp130, the gp130-associated protein tyrosine kinases Jak1,Jak2, and Tyk2, the phosphotyrosine phosphatase PTP1D/Syp, the adaptor protein Shc and the mitogen-activated protein kinase Erk2, and accumulation of GTP-bound p21ras. Prior treatment of U266 cells with IFN-beta downregulated IL-6-induced tyrosine phosphorylation of gp130, Jak2, PTP1D/Syp, Shc, and Erk2, and GTP-loading of p21ras. Further analysis indicated that treatment with IFN-beta disrupted IL-6-induced binding of PTP1D/Syp to gp130 and the adaptor protein Grb2; IFN-beta pretreatment also interfered with IL-6-induced interaction of Shc with Grb2 and a 145-kD tyrosine-phosphorylated protein. These results suggest a novel mechanism whereby type I IFNs interrupt IL-6-promoted mitogenesis of myeloma cells in part by preventing the formation of essential signaling complexes leading to p21ras activation.
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PMID:Interferon-beta interrupts interleukin-6-dependent signaling events in myeloma cells. 897

Vav is a hematopoietic cell-specific proto-oncogene. We show that interleukin-6 (IL-6) induces transient tyrosine phosphorylation of Vav in a human myeloma cell line, U266. A membrane-distal part of the cytoplasmic region of gp130 is critical for association between Vav and gp130, and the IL-6-induced tyrosine phosphorylation of Vav. Mitogen-activated protein kinase (MAPK) (p42MAPK or extracellular signal-regulated kinase 2 (Erk2)) is coprecipitated with Vav. MAPK activity in the anti-Vav immunoprecipitates is upregulated by IL-6 stimulation. Furthermore Vav is associated with Grb2 which is known as an adapter protein leading to Ras activation. The results imply that Vav may link gp130 activation to downstream MAPK activation in hematopoietic cells.
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PMID:Vav is associated with signal transducing molecules gp130, Grb2 and Erk2, and is tyrosine phosphorylated in response to interleukin-6. 901 73


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