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: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Functional interrelationships between components of nuclear architecture and control of gene expression are becoming increasingly evident. In this article we focus on the concept that association of genes and cognate transcription factors with the nuclear matrix may support the formation and/or activities of nuclear domains that facilitate transcriptional regulation. Several lines of evidence are consistent with the concept that association of transcription factors with the nuclear matrix may be obligatory for fidelity of gene expression and maximal transcriptional activity. The identification of specific regions of transcription factors that are responsible for intranuclear trafficking to nuclear matrix-associated sites that support transcription, reinforces the linkage of nuclear structure to regulation of genes. CBFA2/AML-1 and CBFA1/AML-3 provide paradigms for directing gene regulatory factors to RNA polymerase II containing foci within the nucleus. The implications of modifications in the intranuclear trafficking of transcription factors for developmental and tissue-specific control, as well as for aberrations in gene expression that are associated with cancer and neurological disorders, are addressed.
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PMID:Interrelationships of nuclear structure and transcriptional control: functional consequences of being in the right place at the right time. 967 Dec 26

The two matrix metalloproteinases (MMPs) Mr 72,000 type IV collagenase (MMP-2, gelatinase A) and Mr 92,000 type IV collagenase (MMP-9, gelatinase B) play key roles in tissue remodeling and tumor invasion by digestion of extracellular matrix barriers. We have investigated the production of these two enzymes as well as the membrane-type MMP (MT1-MMP) and the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 in the bone marrow mononuclear cells (BM-MNCs) of patients with acute myeloid leukemia (AML; n = 24), chronic myeloid leukemia (CML; n = 17), myelodysplastic syndromes (MDS; n = 8), and healthy donors (n = 5). Zymographic analysis of BM-MNC-conditioned medium showed that a Mr 92,000 gelatinolytic activity, identified as MMP-9 by Western blotting, was constitutively released from cells of all patients and healthy individuals examined in this study. In contrast, MMP-2 secretion was found to be absent in all samples from healthy donors but present in 8 of 11 (73%) of the samples from patients with primary AML, 7 of 8 (88%) with secondary AML, and only 1 of 5 (20%) cases with AML in remission, indicating MMP-2 to be produced by the leukemic blasts. MMP-2 release was not detected in CML cell-conditioned medium with the exception of two cases, both patients either being in or preceding blast crisis. In MDS, MMP-2 was found in three of eight (38%) of the patients, two of them undergoing progression of disease within 12 months. Quantitative Northern blot analysis in freshly isolated BM-MNCs showed a relatively low constitutive expression of TIMP-1 in all samples, whereas MMP-9 gene transcription was higher in healthy donors and CML samples, than in AML and MDS. Reverse transcriptase-PCR analysis revealed the presence of TIMP-2 mRNA in the majority of MMP-2-releasing BM-MNCs. MT1-MMP expression was present in most samples of patients with MDS or AML but absent in those with secondary AML and CML. Thus, we have shown that BM-MNCs continuously produce MMP-9 and TIMP-1 and demonstrated that leukemic blast cells additionally secrete MMP-2 representing a potential marker for dissemination in myeloproliferative malignancies.
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PMID:Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes. 1035 46

The runt family transcription factor (AML-3/PEBP2alphaA1/Cbfa1/RUNX2) plays a crucial role in formation of the mineralized skeleton during embryogenesis and regulates maturation of the osteoblast phenotype. Because steroid hormones and growth factors significantly influence growth and differentiation properties of osteoblasts, we addressed Cbfa1 as a target gene for regulation by dexamethasone (Dex), 1,25(OH)D(3) (vitamin D(3)), 17beta-estradiol, and transforming growth factor-beta1 (TGF-beta1). The representation of functional protein levels by Western blot analyses and gel mobility shift assays was examined during the growth and mineralization of several conditionally immortalized human osteoblast cell lines HOB 04-T8, 03-CE6, and 03-CE10, each representing different stages of maturation. In situ immunofluorescence demonstrates Cbfa1 is associated with nuclear matrix in punctate domains, some of which are transcriptionally active, colocalizing with phosphorylated RNA polymerase II. Although each of the cell lines exhibited different responses to the steroid hormones and to TGF-beta1, all cell lines showed a similar increase in Cbfa1 protein and DNA binding activity induced only by Dex. On the other hand, Cbfa1 mRNA levels were not altered by Dex treatment. This regulation of Cbfa1 by steroid hormones in human osteoblasts contrasts to modifications in Cbfa1 expression in primary rat calvarial osteoblasts and the mouse MC3T3-E1 osteoblast cell line. Thus, these results reveal multiple levels of regulation of Cbfa1 expression and activity in osteoblasts. Moreover, the data suggest that in committed human osteoblasts, constitutive expression of Cbfa1 may be required to sustain the osteoblast phenotype.
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PMID:Expression and regulation of Runx2/Cbfa1 and osteoblast phenotypic markers during the growth and differentiation of human osteoblasts. 1113 73

Somatostatin, a neuropeptide with multiple activities, exerts its function via G-coupled membrane receptors. Five somatostatin receptor subtypes, sst1-5, have been identified. We have recently established that somatostatin acts as a chemoattractant on normal hematopoietic progenitor cells. Here, we studied the expression of somatostatin receptors (sst) on leukemic cells from 16 AML patients. Using fluorescent somatostatin (Fluo-SS) in flow cytometry, we found that sst are expressed in variable amounts on primary AML cells. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis and immunochemistry revealed that only sst subtype 2 is expressed by AML cells. Using a two-chamber in vitro migration assay, we show that AML cells migrated towards a gradient of octreotide, a stable synthetic analogue of somatostatin. The degree of migration correlated with the cell surface density of sst2 as measured by Fluo-SS binding. These findings indicate that somatostatin influences trafficking of AML cells, which may have implications for the distribution of AML cells in the body and for clinical applications of somatostatin and analogues thereof in the context of AML.
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PMID:Somatostatin induces migration of acute myeloid leukemia cells via activation of somatostatin receptor subtype 2. 1136 65

The patient was a 62-year-old man. His hematological data in April 2000 had shown no abnormalities, but he was referred to our hospital because of a fever and leukocytosis in June 2000. The peripheral blood showed 29.8 x 10(9)/L white blood cells, with 68.0% blasts. A bone marrow aspirate showed hypercellularity with a proliferation of large leukemic blasts. The leukemic cells were positive for CD13 (91%), CD33 (54.8%), CD34 (94.5%), and HLA-DR (97.9%). Some leukemic cells (15.6%) also expressed CD14. Cytogenetic analysis revealed 92,XXYY,t(9;22)(q34;q11)x2 in all 20 metaphase cells. Reverse transcriptase polymerase chain reaction analysis detected the minor BCR/ABL messenger RNA (mRNA) but failed to detect the major BCR/ABL mRNA. The patient achieved complete remission after induction chemotherapy, with no evidence of Philadelphia chromosome (Ph) or minor BCR/ABL mRNA. Ph-positive acute myeloid leukemia (Ph-AML) has rarely been reported. Herein, we report a case of Ph-AML with tetraploidy and review the previously reported Ph-AML cases.
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PMID:Philadelphia chromosome-positive acute myeloid leukemia with tetraploidy. 1184 93

The t(10;11)(p12-14;q14-21) is a non-random translocation that results in the fusion of CALM gene on chromosome 11 with AF10 gene on chromosome 10. This translocation is observed in acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoblastic lymphoma. Here we report a patient with t(10;11) who was diagnosed with AML-M4. Reverse transcriptase-polymerase chain reaction (RT-PCR) assay revealed one type of CALM/AF10 and three types of AF10/CALM fusion transcripts. Sequencing analysis for these RT-PCR products determined the breakpoint in CALM at nucleotide (nt) 1926-1927 and in AF10 at nt 423-424. The latter breakpoint was the same as that identified in three monocytic cell lines carrying t(10;11). After achieving complete remission, the patient developed mediastinal emphysema during the course of consolidation therapy, possibly due to the necrosis of his mediastinal mass. Monocytic leukemias with CALM/AF10 fusion are frequently associated with mediastinal invasion. We need to pay special attention to such a complication, even if the chest X-ray is normal at presentation.
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PMID:Monocytic leukemia with CALM/AF10 rearrangement showing mediastinal emphysema. 1255 19

Although the classic t(8;21) has been reported in 10 pediatric patients with acute myeloid leukemia with eosinophilia (AML M4Eo), no complex variant t(8;21) in children with AML M4Eo has been previously described. In our analysis of leukemic blasts from a 4-year-old boy with AML M4Eo, conventional cytogenetics revealed that 95% of the cells had a hypodiploid line containing 45 chromosomes and a complex karyotype involving chromosomes 3, 8, and 21. Fluorescence in situ hybridization using whole chromosome painting probes for these chromosomes confirmed the cytogenetic findings. The presence of a CBFA2-ETO fusion gene was established by fluorescence in situ hybridization and reverse-transcriptase polymerase chain reaction analysis. Thus, this report illustrates the first description of a complex variant t(8;21) involving chromosome band 3q27 in a child with AML M4Eo.
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PMID:A complex variant t(8;21) involving chromosome 3 in a child with acute myeloblastic leukemia with eosinophilia (AML M4Eo). 1269 Nov 61

Diffuse large B-cell lymphoma (DLBCL) accounts for 30-40% of all adult non-Hodgkin's lymphomas, yet the understanding of its underlying genetic abnormalities remains poor. Our present study used the serological analysis of recombinant cDNA expression libraries (SEREX) technique to identify DLBCL-associated antigens. SEREX screening of testis libraries has previously identified cancer-testis antigens (CTAs) that may act as disease-specific targets for immunotherapy. Screening a testis cDNA expression library with serum from a DLBCL patient identified a total of 94 positive clones, representing 28 distinct antigens. Two of these antigens were novel, 8 were previously uncharacterised, and the remainder were proteins of known function. Screening of the antigens with sera from DLBCL (n = 10), acute myeloid leukaemia (AML, n = 10) and chronic myeloid leukaemia (CML, n = 10) patients, alongside normal healthy donor controls (n = 20), revealed that 7 of the antigens were recognised by DLBCL sera but not normal donor sera, whilst 2 of these antigens were also recognised by leukaemic sera. Some of the genes identified here were already known to be transcribed in DLBCL. The mRNA expression of the majority of the remaining antigens was confirmed in DLBCL cell lines using reverse-transcriptase PCR (RT-PCR). Our study identified a number of DLBCL associated antigens that may be suitable as prognostic/diagnostic markers and/or for the immunotherapy of haematologic malignancies.
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PMID:Serologic detection of diffuse large B-cell lymphoma-associated antigens. 1512 89

A 18-year-old man was diagnosed with acute promyelocytic leukemia (APL). The conventional cytogenetic analysis revealed normal karyotype 46, XY, t(15; 17). Reverse transcriptase polymerase chain reaction (RTPCR) identified PML-RARa chimeric transcripts. Complete remission (CR) was attained with 3 induction courses of Ara-C, daunorubicin and all-trans retinoic acid (ATRA). Three years later the patient relapsed. The blasts in bone marrow aspirate at relapse had AML-M3 morphology, and RT-PCR was positive for PML-RARa transcripts. The patient was treated with ATRA and daunorubicin without success. Two months later the blasts in bone marrow aspirate showed AML-M2 morphology, the karyotype was 47, XY, +8 and RT-PCR revealed the presence of AML1-ETO transcripts and absence of PML-RARa transcripts. The patient attained second CR with 3 induction courses -a course with Ara-C and daunorubicin and 2 courses with idarubicin, Ara-C and etoposide.
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PMID:Clonal heterogeneity in a patient with acute promyelocytic leukemia. 1741 15

Here we report a rare chromosomal translocation, t(12;22)(p13;q11), which was detected in a 53-year-old female patient diagnosed as having minimally differentiated acute myeloid leukemia (AML-M0) according to the French-American-British classification criteria. Chromosome painting analysis with probes for chromosomes 12 and 22 confirmed the result of the conventional cytogenetic analysis. Reverse transcriptase polymerase chain reaction revealed the TEL-MN1 fusion transcript. Interestingly, she presented primary multidrug resistance and did not respond to several kinds of chemotherapy regimens. Moreover, she could not achieve remission after two doses of monotherapy with Mylotarg. Flow cytometry analysis detected high levels of expression of P-glycoprotein, multidrug-resistant-related protein, lung-related protein, and glutathione S-transferase pi in this case at presentation. As far as we know, this is the first report of t(12;22)(p13;q11) translocation involving TEL and MN1 genes in an AML-M0 patient.
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PMID:Minimally differentiated acute myeloid leukemia with t(12;22)(p13;q11) translocation showing primary multidrug resistance and expressing multiple multidrug-resistant proteins. 1747 96


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