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)

Insulin-like growth factors (IGF-I, IGF-II) have long been recognized as important mitogens in many types of malignancies. Because the role of IGFs in growth control of myeloma cells has not been extensively examined, we have used a panel of IL-6-responsive myeloma cell lines to address this issue. Initial studies demonstrated that IGF-I and IGF-II significantly enhanced DNA synthesis by each of the four cell lines, even when assayed in the absence of IL-6. The specificity of the IGF response was confirmed using an IGF-I receptor Ab, and additional studies demonstrated that IGF responsiveness did not result from induction of autocrine IL-6 expression. When IL-6 responsiveness was assayed, three of four cell lines synthesized DNA in response to IL-6 alone; however, the magnitude of responsiveness was greatly enhanced by addition of IGFs. Similar results were obtained when proliferation and cell cycle progression were analyzed. By contrast, the KP-6 cell line was responsive to IL-6 only when IGF was present. Finally, we analyzed the effects of IGF-I on normal B lymphocytes. IGF, however, did not stimulate B cell DNA synthesis, suggesting that IGF responsiveness may represent a key difference between normal and malignant B cells. In summary, these studies suggest that IGFs may play an important role in multiple myeloma by virtue of their ability to directly stimulate tumor cell growth as well as modulate the magnitude of IL-6-driven growth.
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PMID:A role for insulin-like growth factor in the regulation of IL-6-responsive human myeloma cell line growth. 920 Apr 90

Cytokines are polypeptides that bind to membrane receptors and may act in an endocrine, paracrine or autocrine way. Several cytokines and growth factors may be produced by bone cells, stored in the matrix or act on them. Osteoclasts derive from the bone marrow stem cell and, as monocytes, belong to the family of tissue macrophages. Their specific function is bone resorption. Interleukin 1, 6 and 11, transforming growth factor and tumor necrosis factor stimulate osteoclast mediated bone resorption. Interleukin 1 is the most potent bone resorption agent and seems to be identical to osteoclast activation factor, identified in multiple myeloma. The role of interleukin 1, 6, 11 and tumor necrosis factors in postmenopausal osteoporosis triggered by the fall in estrogen levels, has not been well defined yet. Cytokines that increase bone formation are insulin like growth factors I and II, transforming growth factor, platelet derived growth factor and bone morphogenic proteins. Probably, tumor necrosis factor and interferon-gamma have a depressor effect on bone formation. Cytokines and growth factors, liberated from bone cells or from the matrix during osteoclastic work, could be the signals responsible for coupling bone formation and resorption.
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PMID:[Cytokines, growth factors, and metabolic bone disease]. 921 95

Peripheral sensory and autonomic neurons are known to possess insulin receptors. These have been considered to be of the peripheral type, i.e. similar to those of hepatic and fat cells rather than of the brain type which show dual specificity for both insulin and insulin-like growth factor (IGF-1). We have examined the localisation of insulin and IGF-1 receptors in cultured sensory and sympathetic ganglion cells using confocal microscopy and indirect labelling with FITC (fluorescein isothiocyanate) and TRITC (tetramethyl rhodamine isothiocyanate) respectively. We have shown that in cultured U266B1 multiple myeloma cells these receptors display separate localisation, whereas they are colocalised in IM-9 lymphocytes which are known to possess hybrid receptors. We have confirmed the sequestration of insulin and IGF-1 receptors in the cytoplasm of sensory and sympathetic neurons, consistent with a brain-type receptor. The colocalisation of insulin and IGF-1 receptors in sensory and sympathetic ganglion cells is consistent with the view that they are hybrid receptors, similar to those present in the CNS. The function of these receptors, as suggested for the CNS, may be related to trophic support for neurons.
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PMID:Colocalisation of insulin and IGF-1 receptors in cultured rat sensory and sympathetic ganglion cells. 941

POEMS syndrome is a rare synopsis of different multisystemic disorders (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammapathy, and skin lesions) associated with plasma cell dyscrasia. We herein report the atypical case of a 44-year-old white man presenting with glomerulopathy, POEMS syndrome, and erythema elevatum diutinum with a few-year history of non-insulin-dependent diabetes mellitus (NIDDM) and seronegative rheumatoid arthritis (RA) as early manifestations of IgAlambda multiple myeloma. The prescription of 1 mg/kg/day prednisone improved the patient's features dramatically. Skin lesions improved by the association of glucocorticoids and plasma exchange, recurred when plasmapheresis ceased, and remitted when plasma exchange was reintroduced. NIDDM requiring insulinotherapy recurred when corticoids were discontinued and remitted when prednisone was reintroduced. However, prednisone and plasmapheresis had no effect on polyneuropathy, M-paraprotein, and plasma cell dyscrasia in our patient, who developed indolent multiple myeloma a few years later. We thus concluded that POEMS syndrome, steroid-dependent diabetes mellitus, rheumatoid arthritis, RA, and skin vasculitis in our patient were triggered by plasma cell dyscrasia.
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PMID:POEMS syndrome, steroid-dependent diabetes mellitus, erythema elevatum diutinum, and rheumatoid arthritis as extramedullary manifestations of plasma cell dyscrasia. 1007 79

A 73-year-old woman with multiple myeloma experienced four episodes of loss of consciousness, convulsions and profuse sweating whilst she was in the hospital. A thorough investigation in the department of medicine disclosed that with each attack, she had a serum glucose < 1.6 mM L-1, insulin level > 1400 pMol L-1 (N- < 150) and a normal level of serum C-peptide. Since she had no anti-insulin antibodies (which may rarely exist in multiple myeloma), a diagnosis of exogenous injection of insulin was made. A search for a possible perpetrator discovered that the patient had a daughter who was a surgical nurse and who was genuinely concerned whenever she was told that her mother was about to be discharged from the hospital. If she was the perpetrator in the present case, then it is possible that the motive for such an action was to postpone the mother's discharge from hospital. This case is an example of a 'factitious disease by proxy' in an elderly patient. The aim of the present report is to alert the medical personnel to the possibility that Munchausen's syndrome by proxy may also occur in the elderly.
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PMID:Recurrent hypoglycaemia in multiple myeloma: a case of Munchausen syndrome by proxy in an elderly patient. 1009 5

Activation of the caspase proteases by c-Jun N-terminal kinase 1 (JNK1) has been proposed as a mechanism of apoptotic cell death. Here we report that insulin activates caspase-3 by a pathway requiring phosphatidylinositol 3'-kinase (PI3-kinase). JNK1 assays demonstrated that insulin treatment of myeloma cells induced 3-fold activation of JNK1. Inhibition of PI3-kinase with wortmannin and LY294002 blocked insulin-dependent activation of JNK1. Caspase assays demonstrated that insulin increased caspase-3 activity 3-fold and that inhibition of PI3-kinase blocked this effect. Cell death was doubled by insulin and was due to a 3-fold increase in apoptosis of cells in the G1/G0 phase of the cell cycle. Inhibition of PI3-kinase completely blocked this effect. Finally, inhibition of caspase-3 with benzyloxycarbonyl-Asp-2,6-dichlorobenzoyloxymethylketone blocked cell death due to insulin. Taken together, these findings indicate that insulin activates caspase-3 by a PI3-kinase-dependent pathway resulting in increased apoptosis and cell death.
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PMID:Insulin activates caspase-3 by a phosphatidylinositol 3'-kinase-dependent pathway. 1020 40

The growth factor-dependent myeloma cell line OH-2, which has previously been shown to be responsive to interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and lymphotoxin, was examined for response to other growth factors. Enhanced proliferation was found in the presence of IL-10, IL-15, IL-2 and insulin growth factor (IGF)-1. Proliferation was strongest in response to IL-6, intermediate and roughly equipotent in response to IL-15, IL-10 and TNF-alpha, and modest in response to IL-2 and IGF-1. IL-15 was synergistic with TNF-alpha, whereas combinations of IL-15 and the other cytokines were merely additive. IL-15-induced proliferation could not be blocked by neutralizing antibody against gp 130, the common transducer chain of IL-6 and related cytokines. IL-15 and IL-6 prevented apoptosis equally well, both better than TNF-alpha, IL-10, and IGF-1. In four out of six samples of purified primary cells, IL-15 and IL-6 induced proliferation. Furthermore, IL-15 mRNA was detected by RT-PCR in most myeloma cell lines and freshly isolated purified patient samples. IL-15 protein was detectable only in one out of about 20 tested cell supernatants from patients and myeloma cell lines. The OH-2 cell line is multi-responsive to cytokines and is a good system for the study of integration of cytokine signal transduction and growth control in myeloma. IL-15 represents a novel modality of growth regulation in myeloma.
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PMID:Interleukin-15 blocks apoptosis and induces proliferation of the human myeloma cell line OH-2 and freshly isolated myeloma cells. 1044 59

Several signaling pathways are activated by interferon alpha (IFNalpha) in hematopoietic cells, including the Jak-Stat and the insulin receptor substrate (IRS) pathways. It has been previously shown that IFNalpha activates the phosphatidylinositol (PI) 3'-kinase via an interaction of the p85 subunit of PI 3'-kinase with IRS proteins. Other studies have proposed that Stat-3 also functions as an adapter for p85. We sought to identify the major pathway that regulates IFNalpha activation of the PI3'-kinase in hematopoietic cells. Our data demonstrate that IFNalpha induces the interaction of p85 with IRS-1 or IRS-2, but not Stat-3, in various hematopoietic cell lines in which IRS-1 and/or IRS-2 and Stat-3 are activated by IFNalpha. In addition, inhibition of PI 3'-kinase activity by preincubation of cells with the PI 3'-kinase inhibitor LY294002 does not affect IFN-dependent formation of SIF complexes that contain Stat-3. To determine whether phosphorylation of tyrosine residues in the IFN receptor is required for activation of the PI 3'-kinase, we performed studies using mouse L929 fibroblasts transfected with mutated human IFNAR1 and/or IFNAR2 subunits of the Type I IFN receptor, lacking tyrosine phosphorylation sites. The serine kinase activity of the PI-3K was activated by human IFNalpha in these cells, suggesting that phosphorylation of the Type I IFN receptor is not essential for PI3K activation. We then determined whether IFNalpha activates the Akt kinase, a known downstream target for PI 3'-kinase that mediates anti-apoptotic signals. Akt was activated by insulin or IGF-1, but not IFNalpha, in the IFNalpha-sensitive U-266 myeloma cell line. Altogether, our data establish that the IRS pathway and not the Stat pathway, is the major pathway regulating engagement of PI 3'-kinase in hematopoietic cells. Furthermore, the selective activation of Akt by insulin/IGF-1 suggests the existence of distinct regulatory activities of PI3'-kinase in growth factor versus interferon signaling.
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PMID:Interferon-dependent activation of the serine kinase PI 3'-kinase requires engagement of the IRS pathway but not the Stat pathway. 1073 21

HIKE is a highly conserved sequence motif identified as a candidate pleckstrin-homology (PH) domain binding site in Gbeta proteins, protein kinases, ankyrin and kinesin. HIKE motifs occur also in gelsolin, neurogranin, neuromodulin and in the PH domain of Bruton tyrosin kinase (BTK). Phosphatidylinositol-binding sequences more distantly related to HIKE are present in gelsolin, in the G protein-coupled receptor kinase 4 and in Trop-2. HIKE regions have been demonstrated to bind both proteins and lipids, and to regulate the interaction of Gbeta, neuromodulin and the BTK PH domain with downstream effectors and the cell membrane. Remarkably, mutations of the HIKE regions are common in diverse human genetic diseases. Several HIKE mutations in protein kinases lead to constitutive activation and cellular transformation, e.g. in MEN-2B, acute myeloid and mast cell leukemias, hereditary papillary renal carcinomas and multiple myeloma. Kinase-inactivating HIKE mutations cause Hirschsprung's disease, piebaldism, insulin resistance and developmental dysplasias. HIKE mutations in the PH domain of BTK lead to X-linked agammaglobulinemia, and different forms of amyloidosis are caused by mutations of HIKE-bearing molecules, for example gelsolin, Ret and Trop-2. Thus, quite diverse genetic diseases might share common molecular mechanisms. These include altered interactions of the mutated molecules with downstream effectors or the cell membrane, and defects in intracellular transport.
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PMID:Large and diverse numbers of human diseases with HIKE mutations. 1076 24

Insulin-like growth factors (IGF) I and II are potent mitogens for a variety of cancer cells. The proliferative and anti-apoptotic actions of IGF are mediated by the IGF-I receptor (IGF-IR), to which both IGF-I and IGF-II bind with high affinity. To investigate the mitogenic and anti-apoptotic activities of IGF-IR and to achieve better inhibition of IGF-IR function, single-chain antibodies against human IGF-IR (alphaIGF-IR scFvs) were constructed and expressed. IgG cDNA encoding variable regions of light and heavy chains (VL and VH) from mouse IgG were cloned from a hybridoma producing the 1H7 alphaIGF-IR monoclonal antibody [Li et al., Biochem Biophys Res Commun 196: 92-98 (1993)]. The splice-overlap extension polymerase chain reaction was used to assemble a gene encoding the alphaIGF-IR scFv, including the N-terminal signal peptide, VL, linker peptide, VH, and C-terminal DYKD tag. Two types of soluble alphaIGF-IR scFvs, a prototype alphaIGF-IR scFv and its alternative type alphaIGF-IR scFv-Fc, were constructed and expressed in murine myeloma cells. alphaIGF-IR scFv-Fc, containing the human IgG1 Fc domain, was stably expressed in NS0 myeloma cells, using a glutamine synthase selection system, and purified from the conditioned medium of stable clones by protein-A--agarose chromatography. Levels of alphaIGF-IR scFv-Fc expression ranged from 40 mg/l to 100 mg/l conditioned medium. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis under reducing and nonreducing conditions indicated that alphaIGF-IR scFv-Fc is a dimeric antibody. alphaIGF-IR scFv-Fc retained general characteristics of the parental 1H7 monoclonal antibody except that its binding affinity for IGF-IR was estimated to be approximately 10(8) M(-1), which was one-order of magnitude lower than that of 1H7 monoclonal antibody. Injection of alphaIGF-IR scFv-Fc (500 microg/mouse, twice a week) significantly suppressed MCF-7 tumor growth in athymic mice. These results suggest that the alphaIGF-IR scFv-Fc is a first-generation recombinant alphaIGF-IR for the potential development of future alphaIGF-IR therapeutics.
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PMID:Single-chain antibodies against human insulin-like growth factor I receptor: expression, purification, and effect on tumor growth. 1094 7


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