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)

Human interleukin (IL)-5 gene transcription is regulated by several transcription factor binding sites, including CLE 0, GATA, and a region from position -123 to -92 known as response element (RE)-II. By expression cloning, a partial protein was identified that bound to concatamers of RE-II. Recombinant protein derived from this initial complementary DNA (cDNA) encoding the partial protein specifically bound to RE-II-containing oligonucleotides in electromobility shift assays. The complete sequence (3,649 bp) was determined by 5' rapid amplification of cDNA ends and comparisons to existing ESTs, and found to be identical to the 3' half of Wolf-Hirschhorn syndrome candidate 1, (WHSC1; also known as Multiple Myeloma SET domain [MMSET]). The full-length protein contains an SET domain and two plant homeodomain-type zinc fingers. Transcription initiation of RE-II binding protein (RE-IIBP) messenger RNA (mRNA) uniquely occurred within the middle of WHSC1 near a region that exhibits complex mRNA splicing. RE-IIBP reactive polyclonal antisera identified proteins in human T-cell nuclear protein extracts of 62 and 66 kD that were consistent with the length of the longest open reading frame in RE-IIBP. In contrast, WHSC1 is predicted to encode a protein of 136 kD. In activated human Jurkat and murine D10.G4.1 T cells, expression of full-length and truncated forms of RE-IIBP repressed RE-II promoter activity of a 5X-RE-II luciferase reporter construct by as much as 75%. In addition, RE-IIBP expressed in activated D10.G4.1 T cells inhibited endogenous murine IL-5 production. The repressor activity of RE-IIBP is consistent with the presence of an SET domain that is found in other proteins that act as gene silencers.
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PMID:A unique mRNA initiated within a middle intron of WHSC1/MMSET encodes a DNA binding protein that suppresses human IL-5 transcription. 1115 55

Tetra(trifluoroethoxyl) zinc phthalocyanine, which could be dissolved in most organic solvents, was synthesized. The compound displays a good photocytotoxicity on myeloma cells and Chinese hamster ovary cells in vitro in the presence of the emulsifying agent F68.
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PMID:Tetra-trifluoroethoxyl zinc phthalocyanine: potential photosensitizer for use in the photodynamic therapy of cancer. 1174 3

Multiple myeloma (MM) is a clonal neoplasm of plasma cells which offers an excellent model to study multistep molecular oncogenesis. In 20-25% of primary tumors and cell lines examined, cyclin D1 is overexpressed due to the translocation t(11;14)(q13;q32). We have characterized cyclin-dependent kinase inhibitor p15 (CDKN2B), p16 (CDKN2A) and p18 (CDKN2C) deletions in cyclin D1-expressing and non-expressing MM cell lines. p18 was found to be frequently deleted (38%); in some cases p18 deletions coexisted with hemizygous p16 deletion. To examine the function of p18 as a putative tumor suppressor in myeloma cells, a zinc-inducible p18 construct was stably transfected into KMS12, a MM cell line with biallelic p18 and monoallelic p16 deletions as well as cyclin D1 overexpression. Ectopic expression of p18 caused 40-45% growth suppression as determined by trypan blue exclusion and MTS assays. p18 induction also resulted in apoptosis, suggesting that inhibition of the cyclin D1/CDK/pRb pathway in these tumor cells could be a crucial step toward the induction of tumor regression via apoptotic cell death. This cell cycle pathway is thus frequently mutated and provides a potentially novel target for gene therapeutic or pharmacologic approaches to human myeloma.
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PMID:Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis. 1184 Feb 72

The serum of a case of hyperglobulinaemia with negative thymol and zinc sulphate turbidity reactions was studied. The serum when added to pathological sera with high turbidity values brought about a marked reduction in the original turbidity values. Also, the serum did not give the usual copper proteinate precipitate when added to copper sulphate solutions. The anomalous protein fraction responsible for the above properties was isolated from the gamma globulins by precipitation at 28% saturation with ammonium sulphate. It was found to be neither a macroglobulin (Waldenstrom's), a cryoglobulin, nor a collagen protein. Its occurrence in the very gamma globulin fraction which is responsible for many of the turbidity reactions is of great significance in the interpretation of these tests. It is suggested that the normal turbidity and flocculation reactions reported in some cases of multiple myelomatosis might be due to some such anomalous proteins.
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PMID:Isolation of a protective gamma-globulin fraction interfering with the zinc sulphate turbidity test. 1447 82

CPD-N is a cytokine-inducible CPD (carboxypeptidase-D) isoform identified in rat Nb2 T-lymphoma cells. The prototypic CPD (180 kDa) has three CP domains, whereas CPD-N (160 kDa) has an incomplete N-terminal domain I but intact domains II and III. CPD processes polypeptides in the TGN (trans-Golgi network) but the Nb2 CPD-N is nuclear. The present study identified a cryptic exon 1', downstream of exon 1 of the rat CPD gene, as an alternative transcription start site that encodes the N-terminus of CPD-N. Western-blot analysis showed exclusive synthesis of the 160 kDa CPD-N in rat Nb2 and Nb2-Sp lymphoma cells. Several haematopoietic cell lines including human K562 myeloma, Jurkat T-lymphoma and murine CTLL-2 cytotoxic T-cells express a 160 kDa CPD-immunoreactive protein, whereas mEL4 T-lymphoma cells express the 180 kDa CPD. The CPD-immunoreactive protein in hK562 cells is also nuclear and cytokine-inducible. In contrast, MCF-7 breast cancer cells express only the 180 kDa CPD, which is mainly in the TGN. CPD/CPD-N assays using substrate dansyl-L-alanyl-L-arginine show approx. 98% of CPD-N activity in the Nb2 nucleus, whereas MCF-7 CPD activity is enriched in the post-nuclear 10000 g pellet. The K(m) for CPD-N and CPD are 132+/-30 and 63+/-9 microM respectively. Specific activity/K(m) ratios show that dansyl-L-alanyl-L-arginine is a better substrate for CPD-N than for CPD. CPD-N has an optimal pH of 5.6 (due to domain II), whereas CPD has activity peaks at pH 5.6 (domain II) and pH 6.5-7.0 (domain I). CPD and CPD-N are inhibited non-competitively by zinc chelator 1,10-phenanthroline and competitively by peptidomimetic inhibitor DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid. The Nb2 CPD-N co-immunoprecipitated with phosphatase PP2A (protein phosphatase 2A) and alpha4 phosphoprotein. In summary, a cytokine-inducible CPD-N is selectively expressed in several haematopoietic tumour cells. Nuclear CPD-N is enzymatically active and interacts with known partners of CPD.
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PMID:Characterization of a novel, cytokine-inducible carboxypeptidase D isoform in haematopoietic tumour cells. 1591 96

There are many advantages to the use of protein-free media for biologics production, including a reduced risk of viral contamination from animal-derived proteins and simplification of downstream purification. In the course of developing protein-free media for hybridoma and myeloma cells, zinc was found to be an effective replacement for insulin, with no negative impact on viable cell density and antibody production. Transcript profiling using DNA microarrays indicated no major change in the global expression profile between the insulin and zinc-supplemented cultures, which is consistent with their similar growth and metabolic characteristics. Both DNA microarray and quantitative RT-PCR analysis showed increase in insulin receptor substrate 1 (Irs1) expression in zinc-supplemented cultures, while several key genes downstream of Irs1 in the insulin-signaling pathway, such as protein kinase B (PKB/Akt) and 3-phosphoinositide dependent protein kinase 1 (Pdpk1) did not show significant differences at the transcript level. Comparison of transcript profiles from cultures with low versus optimal zinc supplementation implicated the involvement of the insulin-related genes Pax6 and Phas1. Subtle differences were also observed between insulin and zinc in the serine-473 phosphorylation of Akt. Zinc increased serine-473 phosphorylation of Akt, but to a lesser extent than insulin. The phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, totally blocked the effect of both zinc and insulin on Akt activation, indicating the involvement of PI3K in the activation of Akt by zinc, rather than zinc acting on Akt directly. Our results highlight the impact of trace metal supplementation as protein-free media formulations move towards greater chemical definition.
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PMID:Zinc as an insulin replacement in hybridoma cultures. 1622 92

Monoclonal antibodies against lead were generated by immunizing BALB/c mice with lead conjugated to keyhole limpet hemocyanin (KLH) via a bifunctional chelator, S-2-(4-aminobenzyl)diethylenetriamine pentaacetic acid (DTPA). Stable hybridoma cell lines were produced by fusion of murine splenocytes and SP2/0 myeloma cells. One of the hybridomas generated from this fusion (4/7) synthesized and secreted an antibody that bound tightly to Pb2+-DTPA complexes but not to metal-free DTPA. The performance for a competitive inhibition enzyme-linked immunosorbent assay (ELISA) incorporating this antibody was assessed for its sensitivity to changes in pH, ionic strength, and blocking reagents. The cross-reactivities in this ELISA were less than 3% for Fe3+, Cd2+, Hg2+, and Cu2+ and less than 0.3% for Cr3+, Mn2+, Mg2+, In3+, Ag1+, Ni2+, Co2+, Zn2+, Ca2+, Cu1+, and Hg1+. The IC50 value achieved for lead was 2.72 +/- 0.034 microM, showing the detection range of 0.092-87.2 microM and the lowest detection limit of 0.056 +/- 0.005 microM. Recoveries from the analyte-fortified tap water and ultrapure water were in the range of 80-114% . These results indicate that the ELISA could be a convenient analytical tool for monitoring lead residues in drinking water.
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PMID:Characterization of monoclonal antibodies for lead-chelate complexes: applications in antibody-based assays. 1754 20

Insulin is involved in a number of cellular functions, including the stimulation of cell growth, cell cycle progression and glucose uptake and is a common protein supplement in serum-free mammalian cell culture media. However, several trace metals have previously been reported to exhibit insulin-like effects on specific cell types. As a step towards developing chemically-defined, protein-free media for mammalian cells, we tested the effectiveness of five trace metals (cadmium, nickel, lithium, vanadium and zinc) as a replacement for insulin. Four cell lines of biotechnological relevance were used, including the hybridoma CRL1606, the myeloma NS0, and the Chinese hamster ovary cell lines CHO-IFN and CHO-K1. Zinc was found to be an effective insulin replacement for the hybridoma, myeloma and CHO-K1 cells. Cell growth, cell cycle progression and antibody production was not affected by the substitution. Furthermore, no adaptation procedure was required.
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PMID:Evaluation of insulin-mimetic trace metals as insulin replacements in mammalian cell cultures. 1900 48

Dysregulation of cyclin D2 contributes to the pathogenesis of multiple myeloma, and can occur through translocations that activate MAF/MAFB or MMSET/FGFR3. However, cyclin D2 induction can also be seen in the absence of such translocations, such as in patients with hyperdiploid disease, through unknown mechanisms. In UniGene cluster data-mining and ECgene analysis, we found that zinc-finger with KRAB and SCAN domains 3 (ZKSCAN3), a novel transcription factor, is overrepresented in this malignancy, and three consensus ZKSCAN3 binding sites were found in the cyclin D2 promoter. Analysis of a panel of myeloma cell lines, primary patient samples and datasets from Oncomine and the Multiple Myeloma Genomics Portal (MMGP) revealed expression of ZKSCAN3 messenger RNA (mRNA) in a majority of samples. Studies of cell lines by western blotting, and of primary tissue microarrays by immunohistochemistry, showed ZKSCAN3 protein expression in a majority, and in a manner that paralleled messenger levels in cell lines. ZKSCAN3 overexpression was associated with increased gene copy number or genomic DNA gain/amplification in a subset based on analysis of data from the MMGP, and from fluorescence in situ hybridization studies of cell lines and primary samples. Overexpression of ZKSCAN3 induced cyclin D2 promoter activity in a MAF/MAFB-independent manner, and to an extent that was influenced by the number of consensus ZKSCAN3 binding sites. Moreover, ZKSCAN3 protein expression correlated with cyclin D2 levels in cell lines and primary samples, and its overexpression induced cyclin D2. Conversely, ZKSCAN3 suppression using small hairpin RNAs (shRNAs) reduced cyclin D2 levels, and, importantly, inhibited myeloma cell line proliferation. Finally, ZKSCAN3 was noted to specifically bind to oligonucleotides representing sequences from the cyclin D2 promoter, and to the endogenous promoter itself in myeloma cells. Taken together, the data support the conclusion that ZKSCAN3 induction represents a mechanism by which myeloma cells can induce cyclin D2 dysregulation, and contribute to disease pathogenesis.
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PMID:Evidence of a role for the novel zinc-finger transcription factor ZKSCAN3 in modulating Cyclin D2 expression in multiple myeloma. 2105 42

The 26S proteasome is an ATP-dependent proteolytic complex found in all eukaryotes, archaebacteria, and some eubacteria. Inhibition of the 26S proteasome causes pleiotropic effects in cells, including cellular apoptosis, a fact that has led to the use of the 26S proteasome inhibitor, bortezomib, for treatment of the multiple myeloma cancer. We previously showed that in addition to the effects of proteolysis, inhibition of the 26S proteasome causes a rapid decrease in the protein synthesis rate due to phosphorylating alfa subunit of the eukaryotic translation initiation factor 2 (eIF2alpha) by the heme-regulated inhibitor kinase (HRI). In order to test whether inhibition of the 26S proteasome causes the same effect in cancer cells, we have investigated the influence of two commonly used proteasome inhibitors, bortezomib and MG132, on the phosphorylation status of eIF2alpha in B16F10 melanoma and 4T1 breast cancer cells. It was found that both of the inhibitors caused rapid phosphorylation of eIF2alpha. Taking into account that the Hsp70 is a critical component needed for the HRI activation and enzymatic activity, we have tested a possible participation of this protein in the eIF2alpha phosphorylation event. However, treatment of the cells with two structurally different Hsp70 inhibitors, quercetin and KNK437, in the presence of the proteasome inhibitors did not affect the eIF2alpha phosphorylation. In addition, neither protein kinase C (PKC) nor p38 mitogen-activated protein kinase (MAPK) was required for the proteasome inhibitor-induced eIF2alpha phosphorylation; futhermore, both the PKC inhibitor staurosporine and the p38 MAPK inhibitor SB203580 caused enchanced phosphorylation of eLF2alpha. Zinc (II) protoporphyrine IX (ZnPP), an inhibitor of the heme-oxygenase-1 (HO-1), which has also been previously reported to be involved in HRI activation, also failed to prevent the induction of eIF2alpha phosphorylation in the presence of the proteasome inhibitor bortezomib or MG132.
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PMID:Investigation of the eIF2alpha phosphorylation mechanism in response to proteasome inhibition in melanoma and breast cancer cells. 2109 Jan 73


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