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

We previously isolated and sequenced the 5'-flanking region of the mouse CD14 (mCD14) gene (Matsuura, K., Setoguchi, M., Nasu, N., Higuchi, Y., Yoshida, S., Akizuki, S., and Yamamoto, S. (1989) Nucleic Acids Res. 17, 2132). To define the regulatory elements that control expression of the mCD14 gene, we analyzed the structure of the 5' end of the gene, including a region further upstream of that determined previously. Sequentially 5'-deleted, chimeric, and point mutated clones were tested for the ability to stimulate chloramphenicol acetyltransferase. An 8-base pair sequence, TGATTCAC, at position -255, which resembled the consensus sequence of the 12-O-tetradecanoylphorbol-13-acetate-responsive element (TRE), enhanced the expression of the chloramphenicol acetyltransferase gene in macrophage (aHINS-B3) and non-macrophage (glioblastoma G203 and myeloma NS1) cells. The enhancing ability of the TRE-like sequence (TLS), however, was markedly reduced in G203 cells but not in aHINS-B3 cells when the TLS was followed by the sequence immediately downstream. The TLS and sequence immediately downstream were capable of binding nuclear proteins which were unique to aHINS-B3 cells and macrophages, suggesting that these unique protein regulate the specific expression of the mCD14 gene. Binding of AP-1 to the TLS was also found in aHINS-B3 and G203 cells. Although it is uncertain whether AP-1 is involved in expression of the mCD14 gene, the effect of AP-1 in non-macrophage cells was inhibited by a nuclear protein which binds to the sequence immediately downstream of the TLS.
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PMID:Identification of a tissue-specific regulatory element within the murine CD14 gene. 138 28

At fertilization, sperm chromatin decondenses in two stages, which can be mimicked in extracts of Xenopus eggs. Rapid, limited decondensation is followed by slower, membrane-dependent decondensation and swelling. Nucleoplasmin, an acidic nuclear protein, occurs at high concentration in Xenopus eggs and has a histone-binding role in nucleosome assembly. Immunodepleting nucleoplasmin from egg extracts inhibits the initial rapid stage of sperm decondensation, and also the decondensation of myeloma nuclei, relative to controls of mock depletion and TFIIIA depletion. Readdition of purified nucleoplasmin recues depleted extracts. A physiological concentration of purified nucleoplasmin alone decondenses both sperm and myeloma nuclei. We conclude that nucleoplasmin is both necessary and sufficient for the first stage of sperm decondensation in Xenopus eggs.
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PMID:Sperm decondensation in Xenopus egg cytoplasm is mediated by nucleoplasmin. 203 84

A clone selected from a two-cell mouse embryo cDNA library has been sequenced and identified as rig cDNA. The rig gene codes for a highly conserved nuclear protein, which may have a general role in cell growth or replication (Shiga et al.: Proc Natl Acad Sci USA 87:3594, 1990). The quantitative changes in rig mRNA were studied in blot hybridization experiments with total RNA from oocytes and early embryos. The amount and relative abundance of rig mRNA change considerably during early development. There are about 1.6 x 10(4) rig mRNA molecules in a late growth-stage oocyte; this number is reduced to about one-tenth in the ovulated egg but increases about twenty-fold during cleavage through the blastocyst stage. In F9 embryonal carcinoma cells, the relative abundance of rig mRNA is similar to that in blastocysts (about 0.1% of the mRNA population), but it is about eight-fold higher in the mouse myeloma cell line MOPC-104E. The high level of rig mRNA in late growth-stage oocytes suggests that the rig gene product may be important for overall transcriptional activity rather than DNA replication and mitosis. Alternatively, the rig protein may be a storage product of oogenesis and have a role in the initiation of development.
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PMID:Expression of the rig gene in mouse oocytes and early embryos. 206 74

SS-B/La, an ubiquitous nuclear protein of 46-48 kD, is a target antigen of autoantibodies in SLE and Sjogren's syndrome and is involved in the maturation of RNA polymerase III transcripts such as 5S RNA and tRNAs. We have previously shown (14, 15) that SS-B consists of two protease-resistant domains of 23 and 28 kD, with the latter containing the RNA binding site. The epitopes of SS-B/La reactive with human autoantibodies are conserved among several mammalian species examined. BALB/c mice immunized with affinity-purified calf thymus SS-B produce IgG anti-SS-B/La antibodies, which reacted with bovine, human, and rabbit SS-B but not with mouse SS-B/La. The spleen of a mouse with the highest antibody titer was selected for fusion with P3 myeloma. Five IgG1k mAbs (A1-5) were selected by ELISA and immunoblotting. All except A3 reacted with the 28-kD domain. A1, A2, and A3 were capable of immuno-precipitating the 48-kD SS-B protein and its associated RNAs. A1, A2, and A3 also gave fine nuclear speckled staining on human, monkey, bovine, and rabbit cells that was similar in appearance to that with human autoantibodies, but in contrast to staining with human autoantibodies, they did not stain cells from rat, mouse, or rat kangaroo. It appears that human autoantibodies target highly conserved epitopes that can be distinguished from epitopes recognized by immunization-induced murine mAbs. Taken together with other data, it appears that human autoantibodies may be recognizing epitopes that are active or catalytic sites of molecules subserving important cellular functions.
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PMID:Human autoantibody-reactive epitopes of SS-B/La are highly conserved in comparison with epitopes recognized by murine monoclonal antibodies. 244 93

The class II (Ia) major histocompatibility complex antigens are a family of integral membrane proteins whose expression is limited to certain cell types, predominantly B lymphocytes, macrophages, and thymic epithelial cells. In B cells, Ia expression is both developmentally regulated and responsive to external stimuli. The differentiation of early B stem cells to mature B lymphocytes is accompanied by the appearance of cell surface Ia antigens; the transition to plasma cells results in loss of class II gene expression. In Ia-expressing B cells, the T cell-derived lymphokine interleukin-4 (IL-4) increases such expression by an as yet undefined mechanism. Chloramphenicol acetyltransferase gene expression was cis-activated by a region of the Ia A alpha k gene in a B lymphoma line, but not in a myeloma line. A nuclear protein that bound to two sites within this region, upstream from previously described transcription elements, was found in normal spleen cells. This binding activity was also found in spleen extracts from athymic mice, which lack T lymphocytes, and in Ia-positive B lymphocyte tumor cell lines, demonstrating that it is a B cell protein. Further analysis showed the activity to be undetectable in an Ia-negative pre-B cell line and in three plasmacytoma cell lines that are Ia negative. IL-4 treatment of normal and athymic mouse spleen cells greatly increased the binding of this nuclear protein to these two sites, concomitant with increased MHC class II gene transcription. Thus, B cells contain a sequence-specific DNA-binding activity whose level is influenced both by IL-4 and by differentiation signals.
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PMID:A DNA binding protein regulated by IL-4 and by differentiation in B cells. 314 43

DNA-nuclear protein interactions were studied with synthetic recombination signal sequences (RSSs) for immunoglobulin V-J joining. With a gel retardation assay, a DNA-binding protein that specifically interacts with RSSs was detected in nuclear extracts from a pre-B cell line, 38B9. This protein was found in all the recombination-competent pre-B cell lines tested in this study, but not in myeloma, mature T cell, monocyte, or fibroblast cell lines. DNA footprint analysis with dimethyl sulfate demonstrated that the 7-mer region of the RSS was strongly protected when complexed with the binding protein. Furthermore, a single base substitution in the 7-mer region totally abolished the binding. The molecular mechanism of V-J joining is discussed in the context of the RSS-binding protein.
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PMID:A pre-B cell nuclear protein that specifically interacts with the immunoglobulin V-J recombination sequences. 350 Jul 92

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

The nuclear protein Ki-67 is a proliferation index, as it is expressed only by dividing cells. In this study, we investigated the clinical significance of Ki-67 determination on bone marrow biopsies of 35 patients with newly diagnosed multiple myeloma (MM). We examined the correlation of Ki-67 with other MM proliferation-related factors: interleukin-6 (IL-6), IL-10, bone marrow infiltration by plasma cells, serum lactate dehydrogenase (LDH), and beta 2 microglobulin (b2M). Ki-67 expression was also correlated with the survival rate of the patients. The results showed that Ki-67 expression increases with increasing stage of disease according to Durie-Salmon (classification stage III vs. I and II, p < 0.001). Furthermore, infiltration, IL-6, LDH, and b2M increase significantly with advancing stage of disease (p < 0.004). All parameters studied were significantly higher in patients versus controls. Ki-67 correlated with IL-6 (r: 0.422, p < 0.01), LDH (r: 0.437, p < 0.01), and b2M (r: 0.478, p < 0.004). There was a marked difference in survival between patients with MM with Ki-67 greater than 8% and patients with Ki-67 less than 8%, in favor of the latter (p < 0.07). We conclude that Ki-67 determination during routine pathological analysis of bone marrow in newly diagnosed MM could provide useful information about the proliferative activity and prognosis of the disease.
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PMID:Ki-67 proliferation index: correlation with prognostic parameters and outcome in multiple myeloma. 1475 26

The effect and mode of action of the protein kinase C (PKC) inhibitor PKC412 on human multiple myeloma (MM) cell lines (HMCLs) and primary MM cells was explored. We found that PKC412 induced apoptosis of HMCLs and primary MM cells with variable efficacy; however, some activity was seen against all HMCLs and primary MM cells with at least 0.5 microM PKC412. PARP cleavage and decreased PKC activity was observed in all HMCLs tested. Furthermore, PKC412 inhibited C-FOS transcription and nuclear protein expression, induced reactive oxygen species (ROS) production, and induced both sustained C-JUN expression and phosphorylation. The latter was inhibited by cotreatment with the JNK inhibitor SP600125, which similarly abrogated PKC412-induced apoptosis, suggesting that PKC412-induced apoptosis is a JNK-dependent event. PKC412 treatment secondarily induced prosurvival stress responses as evidenced by activation of NFkappaB and increased expression of the heat shock proteins HSP70 and HSP90. Consistent with the former, sequential inhibition of NFkappaB activation with bortezomib or SN50 synergistically enhanced cell killing. Our results demonstrate that PKC412 induces JNK-dependent apoptosis of HMCLs and primary MM cells and that this effect is enhanced by NFkappaB inhibition. The further evaluation of PKC412 in the treatment of MM is justified.
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PMID:PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells. 1703 22

The current most powerful prognostic model in Multiple Myeloma (MM) combines beta-2 microglobulin (b2m) with albumin, corresponding to the International Staging System (ISS). However, the prognosis of patients within the ISS stage I (high albumin and low b2m) may vary. Ki-67 is a nuclear protein associated with cell proliferation. We retrospectively evaluated the percentage of bone marrow plasma cells expressing Ki-67 antigen (Ki-67 index) in a series of 174 untreated MM patients at diagnosis. Median survival was 51, 41 and 20 months respectively, and median Ki-67 index was 3.0%, 6.1% and 6.5% in ISS stages I, II, and III respectively. Independently of ISS, Ki-67 index > or =4% was highly predictive of adverse prognosis. Ki-67 index correlated with markers of intrinsic malignancy and with markers of tumour burden. Within ISS stage I, median survival was of 31 months (RR of death 2.65) in patients with Ki-67 index > or =4%. Eventually, the combination of Ki-67 with b2m produced an efficient prognostic model, which appeared most effective in our series when compared with b2m and KI-67 with chromosome 13 deletion models. In this series, we demonstrated that a proliferation marker provides clear-cut additional survival prognostic information to b2m into the ISS model.
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PMID:Plasma cell growth fraction using Ki-67 antigen expression identifies a subgroup of multiple myeloma patients displaying short survival within the ISS stage I. 1769 3


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