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  • 1
    Keywords: RECEPTOR ; ANGIOGENESIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; INVASION ; tumor ; CELL ; Germany ; human ; KINASE ; TYROSINE KINASE ; DISEASE ; DISEASES ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; PROTEIN ; RNA ; transcription ; TUMORS ; MECHANISM ; mechanisms ; BINDING ; BIOLOGY ; SEQUENCE ; SEQUENCES ; TRANSCRIPTION FACTORS ; IDENTIFICATION ; CHROMATIN ; gene expression ; ASSAY ; Drosophila ; PROMOTER ; MUTATION ; METASTASIS ; REGION ; CANCER-CELLS ; SMALL INTERFERING RNAS ; Jun ; specificity ; METHYLATION ; TRANSCRIPTIONAL REGULATION ; GROWTH ARREST ; CPG METHYLATION ; CELL-GROWTH ; RE ; DEMETHYLATION ; HELA-CELLS ; SOLID TUMORS ; GENE PROMOTER ; TRANSLATION ; LEVEL ; ASSAYS ; PROMOTER METHYLATION ; CANCERS ; ENGLAND ; PROMOTES ; receptor tyrosine kinase ; 5-AZA-2'-DEOXYCYTIDINE ; GAS6 ; UPSTREAM ; ACTIVATOR PROTEIN-2-ALPHA-RELATED FACTOR ; CELL BIOLOGY ; chromatin immunoprecipitation ; SIRNA ; DRIVEN ; 5-aza-2 '-deoxycytidine (5-aza-dC) ; Axl promoter ; Axl receptor tyrosine kinase (RTK) ; PROTEIN-S ; SP-FAMILY ; specificity protein (Sp) ; VASCULAR SMOOTH-MUSCLE
    Abstract: Synopsis Axl is a receptor tyrosine kinase which promotes anti-apoptosis, mitogenesis, invasion, angiogenesis and metastasis, and is highly expressed in cancers. However, the transcriptional regulation of this important gene has never been characterized. The present study was initiated to characterize the promoter, cis-acting elements and promoter methylation driving expression of Axl. The 2.4 kb sequence upstream of the translational start site, and sequential 5'-deletions were cloned and revealed a minimal GC-rich region (-556 to +7) to be sufficient for basal Axl promoter activity in Rko, HCT116 and HeLa cells. Within this minimal region, five Sp (specificity protein)-binding sites were identified. Two sites (Sp a and Sp b) proximal to the translation start site were indispensable for Axl promoter activity, whereas mutation of three additional upstream motifs (Sp c, Sp d and Sp e) was of additional relevance. Gel-shift assays and chromatin immunoprecipitation identified that Sp1 and Sp3 bound to all five motifs, and mutation of all motifs abolished binding. Mithramycin, which inhibits binding of Sp factors to GC-rich sites, dramatically reduced Axl promoter activity and Axl, Sp1 and Sp3 expression. In Drosophila Schneider SL2-cells, exogenous expression of Sp1/Sp3 increased Axl promoter activity. Use of Sp1/Sp3 siRNAs (small interfering RNAs) significantly reduced Axl promoter activity and protein levels in Rko and HeLa cells. Methylation-bisulfite sequencing detected methylated CpG sites within three Sp motifs (Sp a, Sp b and Sp c) and GC-rich flanking sequences, and demethylation by 5-aza-2'-deoxycytidine up-regulated Axl and Sp3 expression in low-Axl-expressing Colo206f/WiDr cells, but not in high-Axl-expressing Rko cells. The results of the present study suggest that Axl gene expression in cancer cells is (1) constitutively driven by Sp1/Sp3 bound to five core promoter motifs, and (2) restricted by methylation within/around Sp-binding sites. This might enhance the understanding and treatment of essential mechanisms associated with cancer and other diseases
    Type of Publication: Journal article published
    PubMed ID: 18522535
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  • 2
    Keywords: APOPTOSIS ; DOWN-REGULATION ; COLORECTAL-CANCER ; EPITHELIAL-CELLS ; RECEPTOR GENE ; HEPATOCELLULAR-CARCINOMA CELLS ; GROWTH-FACTOR EXPRESSION ; TUMOR-SUPPRESSOR PDCD4 ; TRANSCRIPTION FACTOR ZBP-89 ; HUMAN-DIPLOID FIBROBLASTS
    Abstract: Pdcd4 is an important novel tumor suppressor inhibiting transformation, translation, invasion and intravasation, and its expression is downregulated in several cancers. However, little is known about the transcriptional regulation and the promoter of this important tumor suppressor. So far the following is the first comprehensive study to describe the regulation of Pdcd4 transcription by ZBP-89, besides characterizing the gene promoter. We identified the transcriptional start sites of the human pdcd4 promoter, a functional CCAAT-box, and the basal promoter region. Within this basal region, computer-based analysis revealed several potential binding sites for zinc finger binding proteins, especially for Sp-family members and ZBP-89. We identified four Sp1/Sp3/Sp4 binding elements to be indispensable for basal promoter activity. However, overexpression of Sp1 and Sp3 was not sufficient to enhance Pdcd4 protein expression. Analysis in different solid cancer cell lines showed a significant correlation between pdcd4 and zbp-89 mRNA amounts. In contrast to Sp transcription factors, overexpression of ZBP-89 led to an enhanced expression of Pdcd4 mRNA and protein. Additionally, specific knockdown of ZBP-89 resulted in a decreased pcdcd4 gene expression. Reporter gene analysis showed a significant upregulation of basal promoter activity by cotransfection with ZBP-89, which could be abolished by mithramycin treatment. Predicted binding of ZBP-89 to the basal promoter was confirmed by EMSA data, supershift analysis for ZBP-89. Taken together, data for the first time implicate ZBP-89 as a regulator of Pdcd4 by binding to the basal promoter either alone or by interacting with Sp-family members.
    Type of Publication: Journal article published
    PubMed ID: 22111549
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  • 3
    Keywords: ACTIN, actin binding protein, actin polymerization, actin-binding protein, ALPHA-ACTININ, analysis,
    Abstract: An analysis of the primary structure of the actin-binding protein fesselin revealed it to be the avian homologue of mammalian synaptopodin 2 [Schroeter, Beall, Held, and Chalovich (2008) Biochem. Biophys. Res. Commun. 371, 582-586]. We isolated two synaptopodin 2 isoforms from rabbit stomach that corresponded to known types of human synaptopodin 2. The purification scheme used was that developed for avian fesselin. These synaptopodin 2 forms shared several key functions with fesselin. Both avian fesselin and mammalian synaptopodin 2 bound to Ca2+ calmodulin, a-actinin and smooth-muscle myosin. In addition, both proteins stimulated the polymerization of actin in a Ca2+-calmodulin-dependent manner. Synaptopodin 2 has never before been shown to polymerize actin in the absence of a-actinin, to polymerize actin in a Ca2+-calmodulin-dependent manner, or to bind to Ca2+-calmodulin or myosin. These properties are consistent with the proposed function of synaptopodin 2 in organizing the cytoskeleton
    Type of Publication: Journal article published
    PubMed ID: 18588515
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; SURVIVAL ; IN-VIVO ; THERAPY ; GENE ; PROTEIN ; PROTEINS ; AP-1 ; tumour ; BINDING ; BREAST-CANCER ; PROGRESSION ; PROMOTER ; SIGNALING PATHWAYS ; curcumin ; CELLULAR-TRANSFORMATION ; urokinase-receptor ; ENGLAND ; TUMOR-SUPPRESSOR GENES ; Pdcd4 ; characterization ; chorionallantoic membrane (CAM) ; MICRORNA-21 ; microRNA-21 (miR-21)
    Abstract: Curcumin has promising potential in cancer prevention and therapy by interacting with proteins and modifying their expression and activity, which includes transcription factors, inflammatory cytokines, and factors of cell survival, proliferation, and angiogenesis. miR-21 is overexpressed in many tumors, promoting progression and metastasis. In the present study, we examined the potential of curcumin to regulate miR-21, tumor growth, invasion, and in vivo metastasis in colorectal cancer. In Rko and HCT116 cells, we identified two new transcriptional start sites of the miR-21 gene and delineated its promoter region. PMA stimulation induced miR-21 expression via motifs bound with AP-1 transcription factors. Curcumin treatment reduced miR-21 promoter activity and expression in a dose-dependent manner by inhibiting AP-1 binding to the promoter, and induced expression of tumor suppressor Pdcd4, which is a target of miR-21. Curcumin treated Rko and HCT116 cells were arrested in the G2/M phase with increasing concentrations. Furthermore, curcumin inhibited tumor growth, invasion and in vivo metastasis in the chicken-embryo-metastasis assay (CAM). Additionally, curcumin significantly inhibited miR-21 expression in primary tumors generated in vivo in the CAM assay by Rko and HCT116 cells (p〈0.00006; p〈0.035 respectively). Taken together, this is the first report to show that curcumin inhibits the transcriptional regulation of miR-21 via AP-1, suppresses cell proliferation, tumor growth, invasion, and in vivo metastasis, and stabilizes expression of tumor suppressor Pdcd4 in colorectal cancer
    Type of Publication: Journal article published
    PubMed ID: 20815812
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Bioscience reports 11 (1991), S. 387-444 
    ISSN: 1573-4935
    Keywords: chemiosmotic action ; H+ cycle ; Na+ cycle ; coupling ion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The development of membrane bioenergetic studies during the last 25 years has clearly demonstrated the validity of the Mitchellian chemiosmotic H+ cycle concept. The circulation of H+ ions was shown to couple respiration-dependent or light-dependent energy-releasing reactions to ATP formation and performance of other types of membrane-linked work in mitochondria, chloroplasts, some bacteria, tonoplasts, secretory granules and plant and fungal outer cell membranes. A concrete version of the direct chemiosmotic mechanism, in which H+ potential formation is a simple consequence of the chemistry of the energy-releasing reaction, is already proved for the photosynthetic reaction centre complexes. Recent progress in the studies on chemiosmotic systems has made it possible to extend the coupling-ion principle to an ion other than H+. It was found that, in ceertain bacteria, as well as in the outer membrane of the animal cell, Na+ effectively substitutes for H+ as the coupling ion (the chemiosmotic Na+ cycle). A precedent is set when the Na+ cycle appears to be the only mechanism of energy production in the bacterial cell. In the more typical case, however, the H+ and Na+ cycles coexist in one and the same membrane (bacteria) or in two diffeerent membranes of one and the same cell (animals). The sets of $$\Delta \bar \mu H^ + $$ and $$\Delta \bar \mu Na^ + $$ generators as well as $$\Delta \bar \mu H^ + $$ and $$\Delta \bar \mu Na^ + $$ consumers found in different types of biomembranes, are listed and discussed.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Bioscience reports 11 (1991), S. 445-475 
    ISSN: 1573-4935
    Keywords: membrane ; mitochondria ; transport ; chemiosmotics ; ATPase ; channels ; synaptic junctions ; neurotransmitters ; hormones ; P-glycoprotein ; multi-drug resistance ; antibiotics ; ionophores ; oxidative phosphorylation ; cardiac glycosides ; mitochondrial myopathies ; mitochondrial DNA ; ubiquinone ; oxygen radicals ; ageing ; parasites ; diuretics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The concept of chemiosmotic systems arises from the pioneering work of Peter Mitchell on two fronts. One is concerned with the mechanisms by which molecules are transported across membranes which are generally barriers to such transport. These mechanisms are inevitably molecular, and are now yielding their secrets to a combination of structural protein chemistry and molecular biology. The other front is more physiological, and explores the functional relationships between metabolism and transport. Nevertheless, the two fronts form a continuum of mutally related structure and function. Chemiosmotic systems provide a hierarchy of complexity, starting from say a uniporter reconstituted in a chemically defined bilayer, and proceeding to greater complexity in mitochondria, chloroplasts, eukaryotic and prokaryotic cell membranes, and multicellular systems. Their relationship to medicine is profound, because they provide many opportunities for therapeutic intervention. In this paper I present an overview of chemiosmotic systems at different levels of complexity, both molecular and biological, of their involvements in pathology, and of possible pharmacological treatment or prevention of disease.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Bioscience reports 12 (1992), S. 69-76 
    ISSN: 1573-4935
    Keywords: pancreatic islets ; HIT-T15 cells ; 2-ketoisocaproate transport ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The transport of the nutrient secretagogue 2-ketoisocaproate (KIC) was studied in isolated rat pancreatic islets and in the HIT-T15 insulinoma cell line using an oil-filtration technique. In both islets and HIT-T15 cells, KIC uptake was a slow process, not reaching equilibrium within 10 min KIC transport was not dependent upon Na+ in the medium, was not inhibited by α-cyano-4-hydroxy-cinnamate nor by 2-amino-2-norborane carboxylic acid (BCH) and did not appear to be electrogenic. Evidence was obtained to suggest that KIC uptake occurred via passive diffusion into the cell of the undissociated acid species. This possibility was supported by the apparent unsaturability of KIC uptake in HIT-T15 cells. Addition of 10–30 mM KIC to dispersed islets cells or HIT-T15 cells produced a rapid intracellular acidification. In islets, the rate of transport of 10 mM KIC was comparable with oxidation rate of the keto-acid suggesting that uptake could be rate-limiting factor for KIC oxidation and thus stimulated insulin release. However, in HIT-T15 cells, the rate of uptake of KIC greatly exceeded the oxidation rate. The low rate of KIC oxidation could explain the poor secretory response of HIT-T15 cells to KIC
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-4935
    Keywords: glycosyl phosphatidylinositol ; membrane anchor ; human folate binding proteins ; choroid plexus ; milk and semen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Gel filtration studies in the presence of Triton X-100 showed that treatment with phosphatidylinositol-specific phospholipase C reduced the apparent molecular size of the 100 kDa folate binding protein from human milk, choroid plexus and semen to 25 kDa. Cleavage of a hydrophobic glycosly phosphatidylinositol domain (a membrane anchor) inserting the protein into Triton X-100 micelles could account for this phenomenon.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-4935
    Keywords: Insulin secretion ; pancreatic B-cell ; G-protein ; adenylate cyclase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Rat islets express a pertussis toxin sensitive G-protein involved in receptor-mediated inhibition of insulin secretion. This has been assumed previously to represent “Gi” which couples inhibitory receptors to adenylate cyclase. Incubation of islet G-proteins with32P-NAD and pertussis toxin resulted in the labelling of a band of molecular weight 40,000. This band was very broad and did not allow resolution of individual components. Incubation of the radiolabelled proteins with an anti-Go antiserum resulted in specific immunoprecipitation of a32P-labelled band. These results demonstrate that the complement of pertussis toxin sensitive G-proteins in rat islets includes Go.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-4935
    Keywords: insulin ; phospholipase C ; 5′-nucleotidase ; alkaline phosphatase ; glycosylphosphatidylinositol ; pertussis toxin ; plasma membrane, (rat liver)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Insulin treatment of isolated liver plasma membranes induced the release of 5′-nucleotidase and alkaline phosphatase. This effect was maximal at physiological hormone concentrations, being 36% and 17% for 5′-nucleotidase and alkaline phosphatase respectively, and was fully mimicked by the phosphatidylinositol specific phospholipase C (PI-PLC), thus confirming the presence of a glycosyl-phosphatidylinositol anchoring-system for these exofacial enzymatic proteins. The complete inhibition of insulin dependent enzyme release by neomycin is strongly supportive of an involvement of membrane-located PI-PLC activity. In addition, the insulin-like effect on enzyme release induced by the GTP non-hydrolysable analog, GTP-γ-S, and its sensitivity to the pertussis toxin are in favour of a mediatory role exerted by the G proteins system, in the transduction of some actions of insulin.
    Type of Medium: Electronic Resource
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