Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We searched for genes with expressions specific to human monocyte-derived dendritic cells (DCs) using differential display reverse transcription-polymerase chain reaction, and found that N-myc downstream regulated gene 2 (NDRG2), a member of a new family of differentiation-related genes, was expressed in DCs. While DCs derived from CD34(+) progenitor cells also showed strong NDRG2 expression, the corresponding mRNA expression was absent in other cell lines including monocytes, B cells, and NK cells. The inhibition of DC differentiation by dexamethasone or vitamin D(3) treatment down-regulated the expression of the NDRG2 gene in DCs. In addition, gene expression was induced in a myelomonocytic leukemia cell line, which is capable of differentiating into DCs in cytokine-conditioned culture. The level of NDRG2 gene expression in DCs was significantly higher than that of other members of the NDRG gene family. Finally, in contrast to the stable NDRG2 expression in CD40-stimulated DCs, the induction of DC maturation by lipopolysaccharide (LPS) resulted in the down-regulation of NDRG2 gene expression. This down-regulation is likely to be due to a modification and subsequent destabilization of NDRG2 mRNA, because co-treating with actinomycin D and LPS significantly blocked this LPS effect. Taken together, our results indicate that NDRG2 is expressed during the differentiation of DCs, and that NDRG2 gene expression is differentially regulated by maturation-inducing stimuli.
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PMID:Expression and regulation of NDRG2 (N-myc downstream regulated gene 2) during the differentiation of dendritic cells. 1457 61

Derivatives of vitamin D (deltanoids) are well known to have the ability to induce differentiation of a variety of malignant cells, including human leukemia cells, but the signaling pathways that lead to such an outcome are unclear. In this study we investigated the role of the retinoblastoma protein (pRb) and the CCAAT/enhancer-binding protein (C/EBP) beta in 1,25-dihydroxyvitamin D(3) (1,25D(3))-induced monocytic differentiation of human leukemia HL60 cells. It was found that in this system, pRb is up-regulated within 12 h of exposure to the inducer, and the kinetics of its increase parallel the appearance of the early markers of differentiation, CD14 and monocyte-specific esterase. The increase in pRb expression was accompanied by a similar increase in C/EBPbeta protein, and these two proteins coimmunoprecipitated, suggesting formation of a complex. Oligonucleotides antisense to pRb or C/EBPbeta (but not to C/EBPalpha) or containing the C/EBP-binding sequence ("decoys"), all inhibited 1,25D(3)-induced differentiation. Inhibition of signaling by vitamin D receptor or by mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase pathways using pharmacological inhibitors ZK159222, PD98059, or SP600125, respectively, inhibited pRb and C/EBPbeta expression and differentiation in a coordinate manner. In contrast, inhibition of the p38MAPK pathway by SB202190 potentiated differentiation and the up-regulation of pRb and C/EBPbeta. We suggest that 1,25D(3) may signal monocytic differentiation of HL60 cells in a vitamin D receptor-dependent manner that includes activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase MAPK pathways, which then up-regulate pRb and C/EBPbeta expression and in turn initiate the differentiation process.
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PMID:Retinoblastoma protein and CCAAT/enhancer-binding protein beta are required for 1,25-dihydroxyvitamin D3-induced monocytic differentiation of HL60 cells. 1472 47

(23S)-25-Dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647) functions an antagonist of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells [J. Biol. Chem. 274 (1999) 16392]. We examined the effect of vitamin D antagonist, TEI-9647, on osteoclast formation induced by 1alpha,25-(OH)(2)D(3) from bone marrow cells of patients with Paget's disease. TEI-9647 itself never induced osteoclast formation even at 10(-6)M, but dose-dependently (10(-10) to 10(-6)M) inhibited osteoclast formation induced by physiologic concentrations of 1alpha,25-(OH)(2)D(3) (41 pg/ml, 10(-10)M) from bone marrow cells of patients with Paget's disease. At the same time, 10(-8)M of TEI-9647 alone did not cause 1alpha,25-(OH)(2)D(3) dependent gene expression, but almost completely suppressed TAF(II)-17, a potential coactivator of VDR and 25-hydroxyvitamin D(3)-24-hydroxylase (25-OH-D(3)-24-hydroxylase) gene expression induced by 10(-10)M 1alpha,25-(OH)(2)D(3) in bone marrow cells of patients with Paget's disease. Moreover, TEI-9647 dose-dependently inhibited bone resorption induced by 10(-9)M 1alpha,25-(OH)(2)D(3) by osteoclasts produced by RANKL and M-CSF treatment of measles virus nucleocapsid gene transduced bone marrow cells. These results suggest that TEI-9647 acts directly on osteoclast precursors and osteoclasts, and that TEI-9647 may be a novel agent to suppress the excessive bone resorption and osteoclast formation in patients with Paget's disease.
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PMID:Vitamin D antagonist, TEI-9647, inhibits osteoclast formation induced by 1alpha,25-dihydroxyvitamin D3 from pagetic bone marrow cells. 1522 95

The steroid hormone 1 alpha,25(OH)(2)-vitamin D(3) (1,25D) regulates gene transcription through a nuclear receptor [vitamin D receptor (VDR)] and initiation of rapid cellular responses through a putative plasma membrane-associated receptor (VDR(mem)). This study characterized the VDR(mem) present in a caveolae-enriched membrane fraction (CMF), a site of accumulation of signal transduction agents. Saturable and specific [(3)H]-1,25D binding in vitro was found in CMF of chick, rat, and mouse intestine; mouse lung and kidney; and human NB4 leukemia and rat ROS 17/2.8 osteoblast-like cells; in all cases the 1,25D K(D) binding dissociation constant = 1-3 nM. Our data collectively support the classical VDR being the VDR(mem) in caveolae: 1) VDR antibody immunoreactivity was detected in CMF of all tissues tested; 2) competitive binding of [(3)H]-1,25D by eight analogs of 1,25D was significantly correlated between nuclei and CMF (r(2) = 0.95) but not between vitamin D binding protein (has a different ligand binding specificity) and CMF; 3) confocal immunofluorescence microscopy of ROS 17/2.8 cells showed VDR in close association with the caveolae marker protein, caveolin-1, in the plasma membrane region; 4) in vivo 1,25D pretreatment reduced in vitro [(3)H]-1,25D binding by 30% in chick and rat intestinal CMF demonstrating in vivo occupancy of the CMF receptor by 1,25D; and 5) comparison of [(3)H]-1,25D binding in VDR KO and WT mouse kidney tissue showed 85% reduction in VDR KO CMF and 95% reduction in VDR KO nuclear fraction. This study supports the presence of VDR as the 1,25D-binding protein associated with plasma membrane caveolae.
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PMID:The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)2-vitamin D3 in vivo and in vitro. 1527 54

Leukemia is the most common childhood cancer. Trisenox, the active ingredient of which is trivalent arsenic, is the first line of treatment for acute promyelocytic leukemia. Since drug action usually requires uptake of the drug, it is of importance to determine the transport system responsible for Trisenox uptake. Recently, human aquaglyceroporin 9 (AQP9) has been shown to transport As(III) in Xenopus oocytes. In this study we report to show that AQP9 expression modulates the drug sensitivity of leukemic cells. AQP9 was transfected into the chronic myelogenous leukemia cell line K562. The transfectants became hypersensitive to Trisenox and Sb(III). The promyelocytic leukemia cell line HL60 treated with vitamin D showed higher expression of AQP9 and hypersensitivity to Trisenox and Sb(III). This sensitivity was due to higher rates of uptake of the trivalent metalloids by the cell lines overexpressing AQP9. Trisenox hypersensitivity results from increased expression of AQP9 drug uptake system. The possibility of using pharmacological agents to increase expression of AQP9 gene delivers the promise of new therapies for the treatment of leukemia. Thus, drug hypersensitivity can be correlated with increased expression of the drug uptake system. This is the first demonstration that AQP9 can modulate drug sensitivity in cancer.
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PMID:Drug uptake and pharmacological modulation of drug sensitivity in leukemia by AQP9. 1533 39

The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, mediates the biological actions of the active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3). It regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. Recently, VDR was found to respond to bile acids as well as other nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR). The toxic bile acid lithocholic acid (LCA) induces its metabolism through VDR interaction. To elucidate the structure-function relationship between VDR and bile acids, we examined the effect of several LCA derivatives on VDR activation and identified compounds with more potent activity than LCA. LCA acetate is the most potent of these VDR agonists. It binds directly to VDR and activates the receptor with 30 times the potency of LCA and has no or minimal activity on FXR and PXR. LCA acetate effectively induced the expression of VDR target genes in intestinal cells. Unlike LCA, LCA acetate inhibited the proliferation of human monoblastic leukemia cells and induced their monocytic differentiation. We propose a docking model for LCA acetate binding to VDR. The development of VDR agonists derived from bile acids should be useful to elucidate ligand-selective VDR functions.
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PMID:Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative. 1548 43

The Eight twenty-one (ETO) homologues are nuclear repressor proteins including ETO, myeloid-transforming gene-related protein 1 (MTGR1), and myeloid-transforming gene chromosome 16 (MTG16). ETO and MTG16 are both part of fusion proteins resulting from chromosomal translocations associated with acute myeloid leukemia. Expression of these chimeras results in a differentiation block that contributes to the onset of leukemia. In order to elucidate the relation between the ETO homologues and hematopoietic differentiation, we determined the expression of the homologues during differentiation of leukemic and normal hematopoietic cells. Our results showed MTGR1 and MTG16 to be ubiquitously expressed in leukemic cell lines, whereas expression of ETO was observed only in an erythroleukemic cell line. The MTGR1 and MTG16 proteins decreased during all trans-retinoic acid-, but not vitamin D(3)-induced differentiation of leukemic cells. The reduction seemed to reflect a decrease in transcript levels as well as in protein stability. MTGR1 transcripts were ubiquitously expressed in human bone marrow cells. The MTG16 transcripts of CD34(+) progenitor cells were rapidly downregulated by cytokine-induced differentiation into myeloid or erythroid lineages. ETO transcripts, present at very low abundance in CD34(+) progenitor cells, were transiently upregulated during erythroid differentiation. In conclusion, the differential expression of the ETO homologues suggests that they may have a potential role in hematopoietic differentiation.
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PMID:The Leukemia-associated ETO homologues are differently expressed during hematopoietic differentiation. 1567 13

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
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PMID:Noncalcemic actions of vitamin D receptor ligands. 1579 98

Human thioredoxin (TRX) was first identified in human T-cell leukemia virus type I (HTLV-I)-positive T-cell lines and is associated with the pathophysiology of retroviral infections. TRX is a vital component of the thiol-reducing system and regulates various cellular function (redox regulation). Members of the TRX system regulate apoptosis through a wide variety of mechanisms. A family of thioredoxin-dependent peroxidases (peroxiredoxins) protects against apoptosis by scavenging hydrogen peroxide. Thioredoxin 2 is a critical regulator of cytochrome c release and mitochondrial apoptosis; transmembrane thioredoxin-related molecule (TMX) has a protective role in endoplasmic reticulum (ER) stress-induced apoptosis. TRX interacts with apoptosis signal-regulating kinase 1 (ASK1) and is a sensor of oxidative stress. Thioredoxin binding protein-2/vitamin D(3) upregulated protein 1 is a growth suppressor and its expression is suppressed in HTLV-I-transformed cells. Studies of these molecules of the TRX system provide novel insights into the apoptosis associated with retroviral diseases.
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PMID:The thioredoxin system in retroviral infection and apoptosis. 1581 95

Calcitriol is a potent antiproliferative agent against various tumour cells in vitro. Its biological activity is mediated by the vitamin D receptors (VDRs). Here, we present the results of a study on vitamin D3 compounds (calcitriol and its analogue PRI-2191) as potential agents in combined antitumour therapy in vitro. Applying antiproliferative SRB and MTT assays, we measured the growth inhibitory effects of vitamin D compounds applied alone or in combination with either cisplatin or doxorubicin. Next, we examined the correlation of this effect with the presence of nVDR (nuclear VDR). The following cancer cell lines were applied: HL-60 (human leukaemia), SW707 (human colon cancer), A549 (human lung cancer), WEHI-3 (mouse leukaemia). The treatment of tumour cells with the combination of vitamin D compounds and cytostatics decreased the inhibitory concentration 50% (IC50) values compared with the effects of cytostatics applied alone. The synergistic effect was positively correlated with nVDR expression.
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PMID:Correlation between VDR expression and antiproliferative activity of vitamin D3 compounds in combination with cytostatics. 1615 69


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