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A canonical promoter organization of the transcription machinery and its regulators in the Saccharomyces genome.
Venters BJ, Pugh BF
(2009) Genome Res 19: 360-71
MeSH Terms: Base Sequence, Binding Sites, Chromosome Mapping, DNA Polymerase II, Genome, Fungal, Models, Biological, Nucleosomes, Promoter Regions, Genetic, RNA, Antisense, Saccharomyces cerevisiae, TATA-Box Binding Protein, Transcription Factor TFIIB, Transcription Factors, Transcription, Genetic, Transcriptional Activation
Show Abstract · Added March 5, 2014
The predominant organizational theme by which the transcription machinery and chromatin regulators are positioned within promoter regions or throughout genes in a genome is largely unknown. We mapped the genomic location of diverse representative components of the gene regulatory machinery in Saccharomyces cerevisiae to an experimental resolution of <40 bp. Sequence-specific gene regulators, chromatin regulators, mediator, and RNA polymerase (Pol) II were found primarily near the downstream border from the "-1" nucleosome, which abuts against the approximately 140-bp nucleosome-free promoter region (NFR). General transcription factors TFIIA, -B, -D, -E, -F, -H were located near the downstream edge from the NFR. The -1 nucleosome dissociated upon Pol II recruitment, but not upon recruitment of only TBP and TFIIB. The position of many sequence-specific regulators in promoter regions correlated with the position of specific remodeling complexes, potentially reflecting functional interactions. Taken together the findings suggest that the combined action of activators and chromatin remodeling complexes remove the -1 nucleosome after the preinitiation complex (PIC) has partially assembled, but before or concomitant with Pol II recruitment. We find PIC assembly, which includes Pol II recruitment, to be a significant rate-limiting step during transcription, but that additional gene-specific rate-limiting steps associated with Pol II occur after recruitment.
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15 MeSH Terms
Expression of the prostaglandin F receptor (FP) gene along the mouse genitourinary tract.
Saito O, Guan Y, Qi Z, Davis LS, K├Âmhoff M, Sugimoto Y, Narumiya S, Breyer RM, Breyer MD
(2003) Am J Physiol Renal Physiol 284: F1164-70
MeSH Terms: Animals, Autoradiography, Dinoprost, GTP-Binding Proteins, Immunohistochemistry, In Situ Hybridization, Kidney, Mice, Mice, Inbred C57BL, RNA Probes, RNA, Antisense, Receptors, Prostaglandin, Urogenital System, beta-Galactosidase
Show Abstract · Added December 21, 2013
PGF(2alpha) is one of the major prostanoids produced by the kidney. The cellular effects of PGF(2alpha) are mediated by a G protein-coupled transmembrane receptor designated the FP receptor. Both in situ hybridization and beta-galactosidase knocked into the endogenous FP locus were used to determine the cellular distribution of the mouse FP receptor. Specific labeling was detected in the kidney, ovary, and uterus. Abundant FP expression in ovarian follicles and uterus is consistent with previous reports of failed parturition in FP-/- mice. In the kidney, coexpression of the mFP mRNA with the thiazide-sensitive cotransporter defined its expression in the distal convoluted tubule (DCT). FP receptor was also present in aquaporin-2-positive cortical collecting ducts (CCD). No FP mRNA was detected in glomeruli, proximal tubules, or thick ascending limbs. Intrarenal expression of the FP receptor in the DCT and CCD suggests an important role for the FP receptor regulating water and solute transport in these segments of the nephron.
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14 MeSH Terms
The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome.
Loomes KM, Underkoffler LA, Morabito J, Gottlieb S, Piccoli DA, Spinner NB, Baldwin HS, Oakey RJ
(1999) Hum Mol Genet 8: 2443-9
MeSH Terms: Alagille Syndrome, Animals, Calcium-Binding Proteins, Coronary Vessels, Embryo, Mammalian, Extremities, Eye, Heart Defects, Congenital, Humans, In Situ Hybridization, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Kidney, Lung, Membrane Proteins, Mice, Myocardium, Organ Specificity, Proteins, RNA Probes, RNA, Antisense, Serrate-Jagged Proteins, Spine
Show Abstract · Added June 11, 2010
The establishment of the cardiovascular system represents an early, critical event essential for normal embryonic development, and defects in cardiovascular development are a frequent cause of both in utero and neonatal demise. Congenital cardio-vascular malformations, the most frequent birth defect, can occur as isolated events, but are frequently presented clinically within the context of a constellation of defects that involve multiple organs and that define a specific syndrome. In addition, defects can be a primary effect of gene mutations or result from secondary effects of altered cardiac physiology. Alagille syndrome (AGS) is an autosomal dominant disorder characterized by developmental abnormalities of the heart, liver, eye, skeleton and kidney. Congenital heart defects, the majority of which affect the right-sided or pulmonary circulation, contribute significantly to mortality in AGS patients. Recently, mutations in Jagged1 ( JAG1 ), a conserved gene of the Notch intercellular signaling pathway, have been found to cause AGS. In order to begin to delineate the role of JAG1 in normal heart development we have studied the expression pattern of JAG1 in both the murine and human embryonic heart and vascular system. Here, we demonstrate that JAG1 is expressed in the developing heart and multiple associated vascular structures in a pattern that correlates with the congenital cardiovascular defects observed in AGS. These data are consistent with an important role for JAG1 and Notch signaling in early mammalian cardiac development.
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23 MeSH Terms
Stable antisense RNA expression neutralizes the activity of low-density lipoprotein receptor-related protein and promotes urokinase accumulation in the medium of an astrocytic tumor cell line.
Hussaini IM, Brown MD, Weaver AM, Carpenter J, Karns LR, Vandenberg SR, Gonias SL
(1999) Antisense Nucleic Acid Drug Dev 9: 183-90
MeSH Terms: ADP Ribose Transferases, Astrocytes, Bacterial Toxins, Exotoxins, Low Density Lipoprotein Receptor-Related Protein-1, Neoplasms, Nerve Tissue, Protein Binding, RNA, RNA, Antisense, RNA, Messenger, Receptors, Immunologic, Tumor Cells, Cultured, Urokinase-Type Plasminogen Activator, Virulence Factors, alpha-Macroglobulins
Show Abstract · Added March 5, 2014
Low-density lipoprotein receptor-related protein (LRP) binds and internalizes multiple ligands that are structurally and functionally diverse. However, the effects of LRP on cellular phenotype remain unclear. To study LRP in human astrocytic tumor cells, we designed LRP antisense RNA expression constructs in which the antisense cDNA fragment was expressed under the control of the cytomegalovirus (CMV) promoter. U-1242 MG astrocytic tumor cells were transfected with the antisense constructs and cloned from single cells to yield multiple cell lines with decreased LRP expression. Further studies were performed with two cell lines in which LRP antigen was completely eliminated (L(alpha)42) or substantially decreased (Lalpha47), as determined by Western blot analysis. Untransfected U-1242 MG cells and cells that were stably transfected with empty vector (pBK-CMV) bound activated alpha2-macroglobulin (alpha2M) in a specific and saturable manner. The Bmax was about 5000 receptors/cell. Lalpha42 cells did not bind alpha2M, and binding was decreased by >60% in Lalpha47 cells. Lalpha42 and Lalpha47 cells also demonstrated reduced susceptibility to the cytotoxin, Pseudomonas exotoxin A, and accumulated greatly increased levels of urokinase-type plasminogen activator (uPA) in conditioned medium. The accumulation of uPA demonstrates a major role for LRP in the catabolism of this protein in astrocytic tumor cells. The LRP-deficient cell lines, developed using antisense technology, represent a new model system for studying LRP function in astrocytes.
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15 MeSH Terms
Adenoviral-mediated expression of antisense RNA to fibroblast growth factors disrupts murine vascular development.
Leconte I, Fox JC, Baldwin HS, Buck CA, Swain JL
(1998) Dev Dyn 213: 421-30
MeSH Terms: Adenoviridae, Animals, Cytomegalovirus, Defective Viruses, Embryonic and Fetal Development, Endothelium, Vascular, Fibroblast Growth Factor 2, Gene Expression Regulation, Developmental, Genes, Reporter, Genetic Vectors, Mice, RNA, Antisense, Transcription, Genetic, Virus Replication, Yolk Sac
Show Abstract · Added June 11, 2010
Fibroblast growth factors (FGFs) are expressed in the developing embryo and are postulated to regulate embryonic and vascular growth. The goal of this study was to elucidate the role of basic fibroblast growth factor (FGF-2) in early murine embryonic cardiovascular development in the mouse embryo. Gestation day 7.5 embryos were harvested and placed in culture, and 12 hr later replication-defective adenovirus (0.5 x 10(6) plaque forming units) encoding either beta-galactosidase or antisense FGF-2 RNA was injected into the sinus venosus of the cultured embryos. Embryos receiving only replication-defective adenovirus expressing the beta-galactosidase gene continued to develop normally over the next 12 hr. In contrast, those receiving adenovirus encoding antisense FGF-2 RNA displayed marked morphogenetic abnormalities, including cessation of growth and abnormal yolk sac vascular development, even though the embryonic hearts continued to beat. Abnormal development of the yolk sac vasculature was confirmed by microangiography and by histologic examination. Coinjection of virus carrying FGF-2 cDNA in the sense orientation reversed the effects of antisense FGF-2 RNA expression. These results confirm the efficacy of the replication-defective adenovirus for targeting gene expression to the developing vasculature and provide evidence for a critical role of FGF in the normal vascular assembly in the early embryo. Cessation of embryonic growth on expression of antisense FGF-2 RNA was most likely attributable to failure of efficient circulation of the early embryonic blood cells from the yolk sac into the embryo.
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15 MeSH Terms
Abrogation of cisplatin-induced programmed cell death in human breast cancer cells by epidermal growth factor antisense RNA.
Dixit M, Yang JL, Poirier MC, Price JO, Andrews PA, Arteaga CL
(1997) J Natl Cancer Inst 89: 365-73
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Breast Neoplasms, Cisplatin, DNA Adducts, DNA Nucleotidylexotransferase, DNA, Complementary, DNA, Neoplasm, ErbB Receptors, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, RNA, Antisense, Signal Transduction, Transplantation, Heterologous, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
BACKGROUND - Epidermal growth factor receptor (EGF-R) perturbation by receptor ligand(s), e.g., epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), or receptor-specific antibodies accentuates cisplatin-induced toxicity in tumor cells. This sensitization occurs only in tumor cells with high expression of EGF-R but not in those with low expression of EGF-R.
PURPOSE - Therefore, we have studied the role of EGF-R expression on cisplatin-mediated cytotoxicity.
METHODS - MDA-468 human breast cancer cells were stably transfected with a p-chloramphenicol acetyl transferase (pact[p]-CAT) vector containing a 4.1-kilobase full-length antisense EGF-R complementary DNA. EGF-R content was assessed by 125I-EGF binding and EGF-R immunoblot assays. Cisplatin sensitivity was evaluated by (a) colony-forming assay in vitro, (b) xenograft growth in nude mice, (c) cell cycle distribution of propidium iodide-labeled DNA, (d) DNA fragmentation in agarose gels, and (e) terminal deoxynucleotidyl transferase (Tdt) fluorescence in situ. Cisplatin uptake was measured by atomic absorption spectroscopy, and the levels of drug-DNA intrastrand adducts were determined by a dissociation-enhanced fluoroimmunoassay that utilizes an antibody against cisplatin-modified DNA.
RESULTS - Selected clones (MDA-468/AS-EGFR) exhibited more than 90% loss of both 125I-EGF binding and receptor content determined by western blot analysis, whereas clones transfected with the vector alone (MDA-468/p-CAT) had EGF-R levels similar to those of the parent cells. By use of a colony-forming assay, the 1-hour IC50 (i.e., the concentration of drug required for 1 hour to achieve 50% cell kill) for cisplatin was 2 microM or less for parental and vector-transfected clones (n = 4), whereas it was 25 microM or more for all MDA-468/AS-EGFR clones (n = 3). MDA-468/p-CAT clones exhibited internucleosomal DNA fragmentation, enhanced Tdt-end labeling in situ, and G2 arrest 48 hours after a 1-hour incubation with 3-30 microM cisplatin. Under these conditions, apoptosis and G2 arrest were undetectable in all MDA-468/AS-EGFR clones. An MDA-468 subline selected after long-term treatment with a TGF-alpha-Pseudomonas exotoxin A fusion protein 40 lacked EGF binding and also exhibited cisplatin resistance (1-hour IC50: > 30 microM) compared with parental cells. This EGF-R-dependent difference in cisplatin response was confirmed in a nude mouse xenograft model by use of high- and low-EGF-R-expressing cell clones. Total intracellular drug accumulation after a 1-hour cisplatin exposure, as measured by atomic absorption spectroscopy, was identical in both groups of cells. Intrastrand drug-DNA adducts, however, were statistically higher in high EGF-R expressors than in low-EGF-R-expressing clones.
CONCLUSIONS - These data indicate that a critical level of EGF-R signaling, which is amplified in some common human cancers, is necessary for cisplatin-mediated apoptosis in tumor cells and suggest an inhibitory effect of this pathway on the repair of cisplatin-damaged DNA.
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19 MeSH Terms
Gene therapy for the treatment of metastatic breast cancer by in vivo transduction with breast-targeted retroviral vector expressing antisense c-fos RNA.
Holt JT, Arteaga CB, Robertson D, Moses HL
(1996) Hum Gene Ther 7: 1367-80
MeSH Terms: Adolescent, Adult, Aged, Breast, Breast Neoplasms, Clinical Protocols, Female, Genetic Therapy, Genetic Vectors, Humans, Middle Aged, Neoplasm Metastasis, Proto-Oncogene Proteins c-fos, RNA, Antisense, Retroviridae, Transformation, Genetic
Added February 17, 2014
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16 MeSH Terms
Tissue-targeted antisense c-fos retroviral vector inhibits established breast cancer xenografts in nude mice.
Arteaga CL, Holt JT
(1996) Cancer Res 56: 1098-1103
MeSH Terms: Animals, Base Sequence, Breast Neoplasms, Cell Division, Female, Gene Expression Regulation, Neoplastic, Genes, fos, Genetic Vectors, Humans, Mice, Mice, Nude, Molecular Sequence Data, Neoplasm Transplantation, RNA, Antisense, Retroviridae, Transplantation, Heterologous, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
The c-fos proto-oncogene has been implicated as a regulator of estrogen-mediated cell proliferation. We have tested the tissue specificity and antitumor efficacy of a mouse mammary tumor virus-regulated antisense c-fos retroviral vector. Systemically administered vector could be detected in several tissues but was only expressed in breast epithelium, thus supporting targeting to mouse mammary tumor virus-regulated tissues. Ex vivo transduction of 30-70% of MCF-7 human breast cancer cells produced expression of antifos RNA, decreased expression of the c-fos target mRNA, induction of differentiation, and inhibition of s.c. tumor growth and invasiveness. In vivo transduction of established i.p. MCF-7 tumors with a single injection of XM6:antifos inhibited tumor growth in athymic mice with a corresponding inhibition of c-fos, transforming growth factor beta1 and transforming growth factor alpha expression. Four daily injections with the antifos RNA induced a much larger MCF-7 i.p. tumor inhibition, with a marked prolongation of survival in the absence of any host tissue toxicity. These results indicate that inhibition of key nuclear genes such as c-fos may lead to disruption of paracrine factors and an antitumor effect, providing a strategy for cancer gene therapy.
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17 MeSH Terms
Loss of MDCK cell alpha 2 beta 1 integrin expression results in reduced cyst formation, failure of hepatocyte growth factor/scatter factor-induced branching morphogenesis, and increased apoptosis.
Saelman EU, Keely PJ, Santoro SA
(1995) J Cell Sci 108 ( Pt 11): 3531-40
MeSH Terms: Animals, Apoptosis, Carrier Proteins, Cell Adhesion, Cell Survival, Cells, Cultured, Cysts, Dogs, Extracellular Matrix, Hepatocyte Growth Factor, Integrins, Kidney Tubules, Distal, Morphogenesis, RNA, Antisense, Receptors, Collagen, Transfection
Show Abstract · Added March 5, 2014
Cellular interactions with collagen in a model of kidney tubulogenesis were investigated using Madin-Darby canine kidney (MDCK) cells in an in vitro morphogenetic system. MDCK cells adhered to collagen types I and IV in a Mg(2+)-dependent manner, typical of the alpha 2 beta 1 integrin. Collagen-Sepharose affinity chromatography and immunoblotting demonstrated the presence and collagen binding activity of the alpha 2 beta 1 integrin on MDCK cells. To assess the function of alpha 2 beta 1 integrin, MDCK cells were transfected with a plasmid pRSV alpha 2' which allowed the expression of alpha 2-integrin subunit antisense RNA. Three G418-resistant clones showing reduced adhesion to collagen, stable genomic integration of the antisense construct, decreased alpha 2-integrin subunit mRNA and decreased alpha 2-integrin subunit protein expression were selected for analysis in morphogenetic experiments. MDCK cells and plasmid-only control transfectants, cultured in three-dimensional collagen type I gels, showed normal cyst formation, whereas the antisense RNA transfectants showed increased apoptosis and formed small rudimentary cysts. Stimulation with hepatocyte growth factor/scatter factor-containing 3T3 fibroblast-conditioned medium or recombinant hepatocyte growth factor/scatter factor resulted in extensive branching of the preformed control cysts whereas the surviving small cysts formed by antisense expressing cells increased in size but failed to elongate and branch upon stimulation. We conclude that alpha 2 beta 1 integrin collagen interactions play a crucial role in the hepatocyte growth factor/scatter factor-induced tubulogenesis and branching morphogenesis of MDCK cells in collagen gels as well as an important role in cell survival.
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16 MeSH Terms
In situ hybridization and localization of mRNA for the rabbit prostaglandin EP3 receptor.
Breyer MD, Jacobson HR, Davis LS, Breyer RM
(1993) Kidney Int 44: 1372-8
MeSH Terms: Adrenal Glands, Animals, Autoradiography, Female, Gastric Mucosa, In Situ Hybridization, Kidney, RNA, Antisense, RNA, Messenger, Rabbits, Receptors, Prostaglandin E, Tissue Distribution
Show Abstract · Added December 21, 2013
The physiological effects of PGE2 appear to be mediated by at least three different "E-prostanoid" receptors designated EP1,EP2, and EP3. These receptors are differentially activated by structural PGE analogs (such as misoprostol) and each couples to a different signal transduction mechanism. Studies demonstrating that inhibition of water absorption in the collecting duct is mediated by a Gi coupled mechanism, suggests that an EP3 receptor is involved the renal effects of PGE2. We used in situ hybridization to determine the tissue distribution of the rabbit EP3 receptor. [alpha-35S] UTP labeled antisense RNA, comprising transmembrane domains IV through VII, was hybridized to tissue sections. Specific labeling of kidney, stomach and adrenal was observed. In the kidney, medullary thick ascending limb and cortical and medullary collecting ducts were intensely labeled, while no labeling of glomeruli, proximal tubules, or cortical thick ascending limbs was observed. The adrenal gland labeled exclusively in the medulla. In the stomach the gastric epithelial crypts were the predominant site of hybridization, without evidence of labeling of the smooth muscle. These results suggest an important role for the EP3 receptor in mediating PGE2 effects in these tissues.
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12 MeSH Terms