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

The hormone 1alpha,25(OH)(2)-vitamin D(3) (125D) binds to its nuclear receptor (VDR) to stimulate gene transcription activity. Inversion of configuration at C-20 of the side chain to generate 20-epi-1alpha,25(OH)(2)D(3) (20E-125D) increases transcription 200-5000-fold over 125D with its 20-normal (20N) side chain. This enhancement has been attributed to the VDR ligand-binding domain (LBD) having different contact sites for 20N and 20E side chains that generate different VDR conformations. We synthesized 1alpha, 25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3) (Gemini) with two six-carbon side chains (both 20N and 20E orientations). Energy minimization calculations indicate the Gemini side chain possesses significantly more energy minima than either 125D or 20E-125D (2346, 207, and 127 minima, respectively). We compared activities of 125D, 20E-125D, and Gemini, respectively, in several assays: binding to wild-type (100%, 147%, and 38%) and C-terminal-truncated mutant VDR; transcriptional activity (of the transfected osteopontin promoter in ROS 17/2.8 cells: ED(50) 10, 0.005, and 1.0 nM); mediation of conformational changes in VDR assessed by protease clipping (major trypsin-resistant fragment of 34, 34, and 28 kDa). For inhibition of cellular clonal growth of human leukemia (HL-60) and breast cancer (MCF7) cell lines, the ED(50)(125D)/ED(50)(Gem) was respectively 380 and 316. We conclude that while Gemini readily binds to the VDR and generates unique conformational changes, none of them is able to permit a superior gene transcription activity despite the presence of a 20E side chain.
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PMID:Characterization of a novel analogue of 1alpha,25(OH)(2)-vitamin D(3) with two side chains: interaction with its nuclear receptor and cellular actions. 1089 9

We reported a 15-year-old boy with an acute myelomonocytic leukemia and FK 506-induced leukoencephalopathy. He was received FK 506 for graft versus host disease occurred after peripheral blood stem cell transplantation. He, four weeks later, had generalized seizures and consciousness disturbance. The serum level of FK 506 was high (27.5 ng/ml). His brain MRI showed abnormal high intensity areas in the frontal and parietal white matter lesions on T2-weighted images. Neuropathological studies revealed the destruction of myelin sheeths and axons in the cerebral white matter corresponded with abnormal lesions on MRI. There were calcification and mineralization in the small vessel walls of the cortex and white matter. Osteopontin immunoreactivity was detected in the endothelial cells of small vessels. These findings suggest that the vascular damage was involved in the FK 506-induced leukoencephalopathy.
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PMID:[A case of FK 506-induced leukoencephalopathy]. 1186 53

Endometrial receptivity is a prerequisite for blastocyst implantation. During receptivity, the hairy-like epithelial cell microvilli transiently fuse to a single flower-like membrane projection called the 'pinopode'. Scanning electron microscopy in sequential endometrial biopsies shows that pinopodes appear about 1 week after ovulation, and they develop and regress within just 2 days. Interestingly, the cycle days when pinopodes appear can vary by up to 5 days between different individuals. On average, they occur on days 20-21 in natural cycles and earlier (days 19-20) in stimulated cycles. The abundance of pinopodes relates to implantation success and many patients with multiple implantation failures fail to produce pinopodes. Based on these findings, biopsies from candidate embryo recipients have been examined in mock cycles and pinopode numbers and timing of their appearance assessed. A similar cycle follows where embryos are replaced earlier or later, according to the reported timing of pinopode formation. If pinopodes are absent, the cycle can be modified. Accumulating evidence supports their clinical use as a marker to assess endometrial receptivity. Pinopode appearance, loss of steroid receptors and maximal expression of a(v)b(3) integrin, osteopontin and leukaemia inhibitory factor and receptor have been demonstrated in the same biopsy, showing a consistent association of pinopode appearance and other receptivity changes.
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PMID:Endometrial pinopodes: some more understanding on human implantation? 1247 May 60

In mammalian cells, several observations indicate not only that phosphate transport probably regulates local inorganic phosphate (Pi) concentration, but also that Pi affects normal cellular metabolism, which in turn regulates apoptosis and the process of mineralization. To elucidate how extracellular Pi regulates cellular functions of pre-osteoblastic cells, we investigated the expression of type III sodium (Na)-dependent Pi transporters in rat bone marrow stromal cells and ROB-C26 pre-osteoblastic cells. The mRNA expression level of gibbon ape leukemia virus receptor (Glvr)-2 was increased by the addition of Pi in rat bone marrow stromal cells, but not in ROB-C26 or normal rat kidney (NRK) cells. In contrast, the level of Glvr-1 mRNA was not altered by the addition of extracellular Pi in these cells. The induction of Glvr-2 mRNA by Pi was inhibited in the presence of cycloheximide (CHX). Moreover, mitogen-activated protein kinase (MEK) /extracellular-signal-regulated kinase (ERK) pathway inhibitors; U0126 (1.4-diamino-2, 3-dicyano-1, 4-bis [2-amino-phenylthio] butadiene) and PD98059 (2'-Amino-3'-methoxyflavone) inhibited inducible Glvr-2 mRNA expression, but p38 MEK inhibitor SB203580 [4-(4'-fluorophenyl)-2-(4'-methyl-sulfinylphenyl)-5-(4'pyridyl) imidazole] did not inhibit the induction of Glvr-2 mRNA expression, suggesting that extracellular Pi regulates de novo protein synthesis and MEK/ERK activity in rat bone marrow stromal cells, and through these, induction of Glvr-2 mRNA. Although Pi also induced osteopontin mRNA expression in rat bone marrow stromal cells but not in ROB-C26 and NRK cells, changes in cell viability with the addition of Pi were similar in both cell types. These data indicate that extracellular Pi regulates Glvr-2 mRNA expression, provide insights into possible mechanisms whereby Pi may regulate protein phosphorylation, and suggest a potential role for the Pi transporter in rat bone marrow stromal cells.
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PMID:Extracellular inorganic phosphate regulates gibbon ape leukemia virus receptor-2/phosphate transporter mRNA expression in rat bone marrow stromal cells. 1458 42

Osteopontin has been identified as a marker of metastasis formation and its increased expression has been correlated with the malignancy of cancer. In this study we provide evidence that increased expression of osteopontin may also be associated with progression of Bcr-Abl-expressing leukaemia cells. The Bcr-Abl fusion protein, generated by the Philadelphia translocation, is the hallmark of chronic myeloid leukaemia (CML). CML exhibits clinically distinct phases. Advanced disease shows defective differentiation, bone marrow infiltration and drug resistance. The critical signalling mediating this disease progression is unknown. Increased aggressiveness of the disease has been correlated with elevated amounts of Bcr-Abl. We generated a 32D cell line model to study the consequences of different expression levels of Bcr-Abl. Osteopontin was identified by microarray analysis as highly upregulated in cells expressing elevated amounts of Bcr-Abl. Moreover, in high Bcr-Abl expressing cells, an additional 50 kDa isoform of osteopontin was detected. It was found that this protein was secreted and that myeloid progenitor cells also expressed appropriate receptors for autocrine activation. We demonstrated that secretion of osteopontin resulted in enhanced degradation of I kappa B, the inhibitor of NF-kappa B. These data indicate a novel consequence of elevated Bcr-Abl expression, which may contribute to the progression of CML.
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PMID:Autocrine secretion of osteopontin results in degradation of I kappa B in Bcr-Abl-expressing cells. 1572 94

Chronic myeloid leukemia (CML) is caused by the constitutively active Bcr-Abl tyrosine kinase. This fusion protein is generated by the Philadelphia translocation t(9;22). CML is a progressive condition that invariably advances from a drug-sensitive to a drug-resistant, aggressive, acute leukemia. The mechanisms responsible for this progression are largely unknown; however, in many cases, progression is accompanied by an increase in Bcr-Abl expression. Osteopontin (OPN) expression has been shown to be involved in the progression and increased aggression and invasiveness of many solid tumors. Here, we demonstrate that OPN expression is induced in a model of leukemia, and we describe the identification of specific signaling pathways required for the induction of OPN expression by p210 Bcr-Abl. We have determined that high levels of Bcr-Abl activate a signaling cascade involving the sequential activation of Ras, phosphatidylinositol-3 kinase, atypical protein kinase C, Raf-1, and mitogen-activated protein kinase kinase, leading to the ultimate expression of OPN. Our results suggest that these molecules represent a single pathway and also that there is no redundancy in this pathway, as inhibition of any individual component results in a block in the induction of OPN. The data presented here define for the first time the ability of Bcr-Abl to stimulate the expression of OPN and also identify the signaling pathway involved. This may not only prove important in understanding the mechanisms of progression of CML but also highlights a pathway that may prove significant in many other cases of oncogenesis, where OPN expression is implicated.
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PMID:Bcr-Abl regulates osteopontin transcription via Ras, PI-3K, aPKC, Raf-1, and MEK. 1585 38

Early T lymphocyte activator 1 (Eta-1), also known as Osteopontin, is a cytokine produced by macrophages and T lymphocytes. It is involved in the regulation of IL-12 and IL-10 expression in macrophages and stimulates the polarization of T cells to the Th1 subset. Three promoter polymorphisms of the human Eta-1 gene, -443T/C, -156delG/G, -66T/G, were investigated for possible influence on gene expression. Electrophoretic mobility shift assays (EMSA) with nuclear extract from the human myeloid leukaemia premonocyte cell line, THP-1, revealed sequence specific binding of the transcription factor Sp1 to the -66T allele but not the -66G allele, and haplotype -443C/-156G/-66T showed a marked increase in promoter activity of a luciferase reporter gene. Thus, a substitution of the T-base with G at position -66 in the Eta-1 promoter modulates the promoter activity of the Eta-1 gene, which might influence the Th1 versus Th2 balance. These observations are discussed in relation to a recently reported related observation on the same gene, and it is argued that discrepancies between reporter gene assays in the two studies may be due to the use of different cell lines and may reflect requirements for different transcription factors in cells involved in immune responses compared with other cells.
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PMID:A functional polymorphism in the Eta-1 promoter is associated with allele specific binding to the transcription factor Sp1 and elevated gene expression. 1600 26

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.
Leukemia 2005 Nov
PMID:The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. 1607 95

Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138(+) cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.
Leukemia 2005 Dec
PMID:Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients. 1620 9

Our earlier studies showed that the apoptosis of renal tubules can be induced by sodium fluoride (NaF). The present study was designed to estimated the effects of B-cell lymphoma/leukemia 2 (Bcl-2), Bcl-2-associated protein X (Bax), and osteopontin (OPN) on the apoptosis of renal tubular cells induced by NaF at different levels. The technique of reverse transcription-polymerase chain reaction and densitometer scanning volume density were used to evaluate the changes of Bcl-2, Bax, and OPN mRNA in tubular cells treated with different doses of NaF (0, 1, 5, 7.5, 12.5 mgF-/L) for 48 h. Compared to control, the level of Bax mRNA significantly increased at cells of the 7.5- and 12.5-mg F-/L groups and the expression of Bcl-2 mRNA obviously decreased at cells of the 5- and 7.5-mg F-/L groups. The NaF also enhanced the expression of OPN mRNA in a dose-dependent manner, but the strongest expression of OPN mRNA was observed at cells of the 7.5-mg F-/L group. The results suggested that NaF induces the apoptosis in renal tubules via activation of the Bax expression and Bcl-2 suppression; OPN probably acts as protective role against apoptosis in fluoride-treated renal cells.
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PMID:Effect of sodium fluoride on the expression of bcl-2 family and osteopontin in rat renal tubular cells. 1638 3


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