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1
Lau, Stephen S. K. "Gene silencing in mammalian cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ28435.pdf.
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Ho, Thien Xuan. "Antiviral gene silencing in plants." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509958.
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Tufarelli, Cristina. "Activation and silencing of α globin expression." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365741.
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Markowetz, Florian. "Probabilistic models for gene silencing data." [S.l.] : [s.n.], 2005. http://www.diss.fu-berlin.de/2006/247/index.html.
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Brown, Stephen. "Transgene mediated gene silencing in tomato." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339677.
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Mason-Suares, Heather Marie. "Polycomb Silencing of the Thor Gene." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1277323215.
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Payne, Richard. "Gene discovery in Catharanthus roseus using virus induced gene silencing." Thesis, University of East Anglia, 2015. https://ueaeprints.uea.ac.uk/59379/.
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This thesis presents the use of Virus Induced Gene Silencing (VIGS) for the discovery of enzymes and transporters involved in monoterpene indole alkaloid (MIA) metabolism in the medicinal plant Catharanthus roseus. C. roseus is the source of a number of MIAs that are used as chemotherapeutic agents in the treatment of a variety of cancers, however the complete biosynthetic pathway for these metabolites remains to be elucidated. Additionally, this metabolic pathway is subcellulary compartmented with the key branch point enzyme, strictosidine synthase, localised to the plant vacuole. There is therefore a need for the import of the substrates for strictosidine biosynthesis; secologanin and tryptamine, across the vacuolar membrane, and export of the product, strictosidine, for synthesis of the downstream alkaloids. This thesis presents the identification of two proteins that act as trans-tonoplastic transporters in MIA metabolism. The multidrug and toxic compound extrusion (MATE) protein, CrMATE1952, was localised to the vacuolar membrane and silencing its expression in planta resulted in the accumulation of a secologanin derivative. This implicates CrMATE1952 in the transport of secologanin into the vacuole and highlights the importance of the spatial organisation of the pathway in preventing secologanin derivatisation. Secondly silencing the expression of a tonoplast localised nitrate/peptide (NPF) transporter, CrNPF2.9, resulted in the 20-fold accumulation of strictosidine, suggesting this transporter is the exporter of strictosidine from the vacuole. Furthermore, VIGS also allowed the identification of a reticuline oxidase like protein, CrRO, which resulted in the accumulation of two new MIAs in leaf tissue upon silencing. This thesis highlights a reverse genetics strategy for gene identification in metabolic pathways and is the first time the MATE and NPF transporters, and the reticuline oxidase like enzymes, have been shown to be involved in MIA metabolism in C. roseus.
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Walker, C. "Gene silencing and development in Phytophthora infestans." Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590982.
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In order to investigate whether epigenetics plays a role in P. infestans, the expression patterns of genes involved in transcriptional and post-transcriptional gene silencing were investigated and several were found to be up-regulated in both pre-infection stages and in planta. A histone deacetylase (Pi-HDA1) was selected for functional characterization using RNA interference (RNAi). Silencing Pi-HDA1 produced large aberrant zoospores indicating that it may be required for development. In addition silencing of Pi-HDA1 resulted in reactivation of INF1 production in inf1-transgenic silenced strains, therefore suggesting that Pi-HDA1 may be directly involved in the silencing of inf1 in inf1-transgenic silenced strains. In addition an RNA helicase, Pi-RNH1 was also found to be specifically up-regulated in zoospores. Pi-RNH1-silenced strains produced large aberrant zoospores that had undergone partial cleavage and often had multiple flagella on their surface. The Pi-RNH1-silenced zoospores were also sensitive to osmotic pressure and they often ruptured upon release from the sporangia. These findings indicate that Pi-RNH1 has a major function in zoospore development. In addition the mechanism of internuclear gene silencing was further investigated. In P. infestans internuclear gene silencing is a process where silencing is transmitted from nucleus to nucleus in heterokaryotic strains. Previously it was demonstrated that internuclear gene silencing is a transcriptional silencing process. In several eukaryotes transcriptional silencing has been shown to involve methylation of cytosines. Methylation sensitive sequencing was performed and it was concluded that DNA methylation is not involved in transcriptional silencing in P. infestans. In solution hybridization assays provided preliminary evidence that small RNAs may be the diffusible factor responsible for the spread of silencing.
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Christopher, Sibley. "Novel gene silencing strategies for Parkinson's disease." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540276.
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Bottley, Andrew. "Patterns of gene silencing in hexaploid wheat." Thesis, University of East Anglia, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445520.
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Lynch, Catherine Anne. "Mechanisms of epigenetic gene silencing in tumourigenesis." Thesis, University of Ulster, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428611.
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Schafer, David Gerald. "Mechanisms underlying epigenetic gene silencing in maize." Thesis, University of Warwick, 2013. http://wrap.warwick.ac.uk/60414/.
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Higher organisms can regulate gene expression through changes in epigenetic marks present on the genome. However, how this regulation takes place in organisms with highly repetitive/complex genomes is not well understood. The acquisition of de novo DNA methylation in plants is mediated by siRNAs through the RNAdirected DNA methylation (RdDM) pathway. The targeted deposition of DNA methylation by this pathway allows for the transcriptional silencing of transposable elements and repeat sequences within the genome, as well as regulating gene expression. In addition, it has been hypothesized that mobile siRNAs may be involved in the epigenetic communication between different seed components. Thus the mobility of non-coding RNAs from extra-embryonic tissues could contribute to epigenetic modifications that could be transmitted to the offspring. The aim of my thesis is to characterise the mechanisms involved in epigenetic gene silencing in maize through the use of a novel transgenic reporter. My work has identified components of the RdDM pathway to be involved in maintenance of gene silencing and show that imprinting and paramutation could be recapitulated using synthetic transgenes. In addition, I developed a novel grafting technique to demonstrate that epigenetic gene silencing could be efficiently transmitted between different seed components. Collectively, this work provides an insight into the complex mechanisms that regulate gene expression in the highly repetitive/complex genome of maize.
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Krenz, Björn. "Gene Silencing und das Abutilon Mosaik Virus." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-32318.
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Raponi, Mitch Biochemistry & Molecular Genetics UNSW. "Antisense RNA-mediated gene silencing in fission yeast." Awarded by:University of New South Wales. Biochemistry and Molecular Genetics, 2001. http://handle.unsw.edu.au/1959.4/18277.
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The major aims of this thesis were to investigate the influence of i) antisense gene location relative to the target gene locus (?????location effect?????), ii) double-stranded RNA (dsRNA) formation, and iii) over-expression of host-encoded proteins on antisense RNA-mediated gene regulation. To test the location effect hypothesis, strains were generated which contained the target lacZ gene at a fixed location and the antisense lacZ gene at various genomic locations including all arms of the three fission yeast chomosomes and in close proximity to the target gene locus. A long inverse-PCR protocol was developed to rapidly identify the precise site of antisense gene integration in the fission yeast transformants. No significant difference in lacZ suppression was observed when the antisense gene was integrated in close proximity to the target gene locus, compared with other genomic locations, indicating that target and antisense gene co-localisation is not a critical factor for efficient antisense RNA-mediated gene suppression in vivo. Instead, increased lacZ down-regulation correlated with an increase in the steady-state level of antisense RNA, which was dependent on genomic position effects and transgene copy number. In contrast, convergent transcription of an overlapping antisense lacZ gene was found to be very effective at inhibiting lacZ gene expression. DsRNA was also found to be a central component of antisense RNA-mediated gene silencing in fission yeast. It was shown that gene suppression could be enhanced by increasing the intracellular concentration of non-coding lacZ RNA, while expression of a lacZ panhandle RNA also inhibited beta-galactosidase activity. In addition, over-expression of the ATP-dependent RNA-helicase, ded1, was found to specifically enhance antisense RNA-mediated gene silencing. Through a unique overexpression screen, four novel factors were identified which specifically enhanced antisense RNA-mediated gene silencing by up to an additional 50%. The products of these antisense enhancing sequences (aes factors), all have natural associations with nucleic acids which is consistent with other proteins which have previously been identified to be involved in posttranscriptional gene silencing.
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Sleutels, Frank Jozefus Godefridus Thomas. "Imprinting and gene silencing are in the Air." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2001. http://dare.uva.nl/document/59847.
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Bannister, Kirsty. "Nuclear organisation and the epigenetics of gene silencing." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446561.
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Pike, Joanna Elizabeth. "Gene silencing mediated by genome targeted histone deacetylation." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289869.
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Wright, Edward. "Silencing of human cytomegalovirus immediate early gene expression." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620032.
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Costa, Ana Margarida Silva Bexiga. "Gene silencing strategies for functional genomics in homobasidiomycetes." Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443704.
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McMaster, S. "Studies on Gene Silencing in Plant Parasite Nematodes." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501370.
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Della, Vedova Chris. "RNA silencing of an endogenous gene in maize /." free to MU campus, to others for purchase, 2004. http://wwwlib.umi.com/cr/mo/fullcit?p3144411.
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Gruber, Jens. "Functional gene analysis in cultured vertebrate cells using siRNA mediated gene silencing." Doctoral thesis, [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975116932.
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Pendergraff, Hannah Michelle. "Impact of oligonucleotide chemistry and silencing mechanism on applications in gene silencing and genome editing." Thesis, University of Southampton, 2016. https://eprints.soton.ac.uk/392926/.
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Endogenous gene regulation is an essential tool for the survival of all organisms. In recent years, scientists have gained valuable mechanistic insight into these endogenous gene regulation pathways. Using synthetic oligonucleotides (chemically modified DNA or RNA), we have been able to tap into these pathways and manipulate gene expression. The development of techniques such as solid phase synthesis have enabled researchers to make custom-made oligonucleotides quickly and efficiently. Although solid phase synthesis is a routine method of obtaining oligonucleotides, more complicated oligonucleotides, e.g. chemically modified or longer RNAs, require optimization of the synthesis cycle and deprotection methodology. In order to synthesize complex oligonucleotides in high yield and purity, we tested several synthesis reagents, cycles, deprotection conditions, and purification methods. Using these optimized conditions, we have successfully synthesized a variety of oligonucleotides for gene silencing and genome editing applications. For synthesis of locked nucleic acid (LNA)-containing phosphorothioate oligonucleotides, tetraethylthiuram disulphide (TETD) is insufficiently reactive but 3-Ethoyx-1,2,4-dithiazoline-5-one (EDITH) gives excellent results. ADAM33 is a susceptibility gene for asthma and bronchial hyperresponsiveness and is implicated in airway remodeling, but its function is only partially understood. Oligonucleotide-mediated gene silencing of ADAM33 could provide valuable insight to its biology and allow us to observe airway development under low ADAM33 expression levels. We show potent silencing of ADAM33 in MRC-5 lung fibroblasts using four different classes of oligonucleotides: siRNAs, single-stranded siRNAs, LNA gapmers, and novel conjugates of antisense oligonucleotides. We observed that several LNA gapmers showed subnanomolar potency when transfected with a cationic lipid, and low micromolar potency when delivered gymnotically. Also, we observed that RNase H-dependent antisense oligonucleotides greatly outperformed RISC-dependent oligonucleotides for silencing ADAM33. As ADAM33 mRNA is 95% retained in the nucleus, this work is consistent with recent findings that antisense oligonucleotides are often more potent against nuclear-localised transcripts. Single-stranded siRNAs (ss-siRNAs) are chemically modified single stranded oligonucleotides that engage the RISC complex, they have the potential to combine the advantages of both duplex siRNAs and antisense oligonucleotides. One disadvantage of the published single-stranded siRNA chemical modification scheme is the use of 2’-O-methoxyethyl-RNA at the 3’ terminus. This modification is not available to most researchers so the use of the ss-siRNA technology has been limited up to the present. During our ADAM33 work, we observed that making small changes to the 3’ terminus of our single-stranded siRNAs could greatly improve the potency of the oligonucleotide. We found that replacing the 3’ terminal 2’-O-methoxyethyl residues with the commercially available 2’-O-methyl or LNA modifications actually improved the potency of the single-stranded siRNA against ADAM33. We developed and optimized single-standed siRNAs based on four additional active siRNA duplex sequences targeting different genes within mammalian cells. In one additional gene, PR, we were able to support our ADAM33 findings that single-stranded siRNAs show improved potency with 2’-O-methyl or LNA modification at the 3’ terminus. However, the single-stranded siRNAs against three target genes in two HEK-293 cell lines failed to show any gene silencing activity with any 3’ terminus modification. The failure of the oligonucleotides could be related to the specific cell lines used for the experiments as we also observed increased toxicity with our single-stranded siRNAs in these cells compared to their parent siRNA duplex. Additionally, as chemically modified oligonucleotides can be used to provide greater affinity and specificity to their target sequence, we wanted to explore whether chemical modifications can improve DNA cleavage activity and specificity for genome editing applications. For this work, we used the clustered regularly interspaced short palindromic repeats/crispr associated (CRISPR/Cas9) type II system, which is commonly used in genome editing applications as it requires only two guide RNAs (crRNA, tracrRNA) and a single protein (Cas9 nuclease) for cleavage of a target dsDNA. We wanted to explore whether the use of chemically modified crRNA could improve the specificity or efficiency of cleavage of target DNA when compared to an unmodified crRNA. However, as no work has been published on chemically modified crRNAs, it was unknown whether the CRISPR/Cas system could tolerate chemical modifications and retain cleavage ability. Using a variety of chemically modified crRNAs, we were successfully able to obtain cleavage of our target DNA sequence, although none of our chemically modified crRNAs were able to match the cleavage efficiency of our unmodified crRNA.
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Starkus, Laura. "Virus-induced gene silencing of putative Diuraphis noxia (Kurdjumov) resistance genes in wheat." Thesis, Manhattan, Kan. : Kansas State University, 2010. http://hdl.handle.net/2097/4193.
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Kardooni, Hoda. "Epigenetic silencing of gene expression in paediatric malignant astrocytoma." Thesis, University of Wolverhampton, 2015. http://hdl.handle.net/2436/615001.
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Brain tumours account for the most frequent type of solid tumours among children. Despite advances in surgery and chemotherapy, brain tumours are still the main cause of cancer deaths in children. Furthermore, little is known about DNA methylation changes in paediatric astrocytoma. Recent investigations suggest that many tumours are initiated not only by genetic abnormalities, but also caused by epigenetic changes. DNA methylation is a key epigenetic mechanism that controls the regulation of gene expression. Interestingly, unlike DNA mutations, epigenetic abnormalities are reversible. The reversibility of epigenetic abnormalities upon pharmacological unmasking has prompted interest in developing epigenetic therapy with the crucial goal of restoring the expression of aberrantly silenced genes. The focus of this study was to utilise a combination of different microarray strategies to develop an integrative candidate gene approach to identify several novel frequently methylated genes in a cohort of paediatric HGA (High grade glioma) samples. In addition, to investigate the potential of therapeutic efficacy of a DNA methyltransferase inhibitor, 5-Aza-dC in paediatric HGA. There were 147 genes commonly identified to be potentially methylated in IN699 cells using the two different array strategies integration; re-expression array and Illumina Infinium Human Methylation 450k array. Furthermore, using two complementary microarray strategies including methylation 450k array and expression array, this work identified 55 genes that were both methylated and under-expressed in these HGA cultures. Following validation with CoBRA and RT-PCR coupled with the response of hypermethylated promoters to the demethylating agent 5-Aza-dC, six novel genes (CXCL14, PRR5L, ELTD1, ITGA2, KRT8 and NTM) that are frequently silenced in paediatric astrocytoma were identified. This study suggests that re-expression of ii CXCL14 inhibited the colony formation and cell growth and reduces the migration rate significantly in IN699 short term culture and likely have functional significance in the development of paediatric HGA and an excellent candidate gene for further analysis. In parallel, the efficacy of 5-Aza-dC treatment was examined in paediatric HGA aiming to introduce this epigenetic therapy as a potential mechanism in management of this tumours. This study demonstrated that, relatively low dose of 5-Aza-dC sharply reduced the colony formation and inhibited proliferation and not through the apoptotic effect. It is likely that this reduction in proliferation without cell death is due to using relatively low doses that do not acutely kill cells, thus, allow the sustained alterations in both gene expression patterns and appearance of a new phenotype to emerge. Taken together, this work contributes to a more detailed understanding of the effect of epigenetic silencing on paediatric HGA. This investigation also demonstrated the use of epigenetic drug, 5-aza-dC to reverse the gene silencing for the potential treatment of paediatric HGA.
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Cruickshanks, Hazel Anne. "Conserved chromatin-mediated gene silencing in yeast and plants." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/26421.
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Cells must regulate gene expression to control development, differentiation, and respond to changes in the environment. The simplistic view of gene regulation states that an activator or repressor molecule binds to a specific sequence in DNA and exerts its effects upon transcription. However, the situation becomes more complicated when we consider that eukaryotic DNA is packaged into chromatin. Chromatin must be modified in order to control gene expression. Cells have adopted many ways of achieving this including: chromatin remodelling, DNA methylation and histone modification. The exact contribution of each of these need to be elucidated in order to fully understand gene regulation. Many common themes run through gene regulation between species, suggesting there are conserved mechanisms of gene control. Using the simple model organism, Saccharomyces cerevisiae, I have studied two types of gene repression found in plant species to compare and further determine their molecular bases. A repetitive DNA fragment previously found to induce de novo methylation and expression variegation in Petunia hybrida, was found to cause gene silencing in S. cerevisiae in a methylation independent manner. The possible mechanisms of this were dissected using gene replacement and protein expression studies. In a separate series of experiments, putative homologues of the S. cerevisiae transcriptional co-repressor, TUP1, were tested for chromatin remodelling ability in yeast. A TUP1 homologue from Arabidopsis thaliana was shown to repress transcription in S. cerevisiae but in a different manner from TUP1 indicating mechanistic similarities and differences between their functions. By using yeast as a tool to study gene regulation in higher eukaryotes, the principles of gene repression can be explored and we can speculate the roles of the individual features such as chromatin remodelling and DNA methylation.
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Shore, Andrew Mark. "Gene Silencing Mechanisms Involved in the Difference of Adipocytes." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502901.
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Haghayegh, Jahromi Neda, and Gheinani Ali Hashemi. "RNA Silencing of Lactate Dehydrogenase Gene in Rhizopus oryzae." Thesis, Högskolan i Borås, Institutionen Ingenjörshögskolan, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:hb:diva-20404.
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RNA silencing with direct delivery of siRNA has been used to suppress ldhA gene expression in filamentous fungus Rhizopus oryzae. Here, for the first time we show that, introducing small interfering RNA which consequently forms silencing complexes can alter the gene expression and we report a significant reduction of lactic acid production for isolates containing short (25 nt) synthetic siRNA. In all samples lactic acid production was reduced comparing with wild types. The average concentration of lactic acid production by Rhizopus oryzae during batch fermentation process where glucose has been used as a sole carbon source, diminished from 2.06 g/l in wild types to 0.36 g/l in knockdown samples which signify 5.7 times decrease. Interestingly, the average concentration of ethanol production was increased from 0.38 g/l in wild types to 0.45 g/l in knockdown samples. In some samples we were able to report even a 10 fold decrease in lactic acid production. Since R.oryzae is capable to assimilate a wide range of carbohydrates hydrolysed from lignocellulosic material in order to produce many economically valuable bulk material such as ethanol, these results suggest that RNA silencing is a useful method for industrial biotechnology to be applied in fungus Rhizopus oryzae in order to trigger the metabolism and gene expression toward a desired product.
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Thakare, Dhiraj, Jianwei Zhang, Rod A. Wing, Peter J. Cotty, and Monica A. Schmidt. "Aflatoxin-free transgenic maize using host-induced gene silencing." AMER ASSOC ADVANCEMENT SCIENCE, 2017. http://hdl.handle.net/10150/623199.
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Aflatoxins, toxic secondary metabolites produced by some Aspergillus species, are a universal agricultural economic problem and a critical health issue. Despite decades of control efforts, aflatoxin contamination is responsible for a global loss of millions of tons of crops each year. We show that host-induced gene silencing is an effective method for eliminating this toxin in transgenic maize. We transformed maize plants with a kernel-specific RNA interference (RNAi) gene cassette targeting the aflC gene, which encodes an enzyme in the Aspergillus aflatoxin biosynthetic pathway. After pathogen infection, aflatoxin could not be detected in kernels from these RNAi transgenic maize plants, while toxin loads reached thousands of parts per billion in nontransgenic control kernels. A comparison of transcripts in developing aflatoxin-free transgenic kernels with those from nontransgenic kernels showed no significant differences between these two groups. These results demonstrate that small interfering RNA molecules can be used to silence aflatoxin biosynthesis in maize, providing an attractive and precise engineering strategy that could also be extended to other crops to improve food security.
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Ding, Xavier. "Mechanisms of microRNA mediated gene silencing in C. elegans /." Basel : [s.n.], 2009. http://edoc.unibas.ch/diss/DissB_8881.
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Bruxner, Timothy J. "Characterisation of mutants influencing epigenetic gene silencing in the mouse." Connect to full text, 2007. http://ses.library.usyd.edu.au/handle/2123/2238.
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Thesis (Ph. D.)--University of Sydney, 2008.Title from title screen (viewed April 1, 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Molecular and Microbial Biosciences. Degree awarded 2008; thesis submitted 2007. Includes bibliographical references. Also available in print form.
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Wang, Hui. "Geminivirus AL2 and L2 proteins interact with and inactivate adenosine kinase." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1078773653.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xvii, 201 p.; also includes graphics (some col.) Includes bibliographical references (p. 171-201). Available online via OhioLINK's ETD Center
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Rinne, Andreas. "Gene silencing using adenoviral RNAi vectors in adult cardiac myocytes." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=979850819.
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Voinnet, Olivier. "Molecular analysis of post-transcriptional gene silencing : mechanisms and roles." Thesis, University of East Anglia, 2001. https://ueaeprints.uea.ac.uk/65118/.
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This work is an investigation of post-transcriptional gene silencing (PTGS) in plants, a process that mediates sequence-specific degradation of RNA. Initially discovered in transgenic plants, PTGS has been long regarded as a curiosity, or even as an artefact of transgenesis. It is shown here that virus-induced gene silencing, in which recombinant viruses carrying element of the host genome trigger PTGS of the corresponding plant gene (Chapter one), is a manifestation of a defence system. This defence is remarkable in its ability to adapt to potentially any virus because its specificity is not genetically programmed by the host but, instead, is dictated by the genome sequence of the viral intruder itself. It is demonstrated in chapters 4 and 5 that PTGS of a transgene can spread in plants from one part to another, indicating the existence of a systemic, sequences-specific silencing signal that is likely to have a nucleic acid component. From the demonstration that replication of potato-virus X also triggers production of a silencing signal in non-transgenic plants (Chapter 8), it is proposed that this long-distance signalling process represents the systemic arm of the host PTGS defence response. Collectively, these findings define the existence of a previously uncharacterised antiviral mechanism in higher plants, which may also operate in animals. This defence holds key features of an elaborate immune system, as it is adaptive, mobile and specific. It is also shown, here, that plant viruses have elaborated counter-defensive measures to overcome the host PTGS response, by producing suppressor proteins that target various steps of the silencing mechanism (Chapters 6, 7). One of these factors, the PYX-encoded p25 protein, had been previously characterised as a facilitator of viral cell-to-cell movement. The finding that p25 specifically inhibits the signalling step of PTGS (Chapter 8) provides a new ground for the investigation of virus movement in plants. In chapter 9, the role of PTGS in plants and its suppression by viruses is discussed in the broader context of plant development and biotechnological applications.
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Bruxner, Timothy James. "Characterisation of mutants influencing epigenetic gene silencing in the mouse." University of Sydney, 2008. http://hdl.handle.net/2123/2238.
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Doctor of Philosophy (PhD)The field of epigenetics emerged primarily from studies in Drosophila, and is now being studied intensively by mammalian biologists. In order to increase our knowledge of epigenetic gene control in the mouse, I have studied modifiers of epigenetic gene silencing. My main method of investigation involved the characterisation of mutants from a sensitised ENU mutagenesis screen performed previously in our laboratory. The screen was carried out in an FVB/NJ strain carrying a variegating GFP transgene expressed in erythrocytes. To date we have recovered 12 dominant (D) and seven recessive (R) mutant mouse lines from this screen that display altered transgene expression. We have named these Mommes (Modifiers of murine metastable epialleles). I investigated the phenotype and attempted to identify the underlying causative mutation of two of these Momme mutants. MommeD6 is a semi-dominant, homozygous lethal mutation that acts as a suppressor of variegation with respect to the GFP transgene. This mutation has a large effect on the level of expression of the transgene in expressing cells, but little effect on the percentage of cells expressing the transgene. MommeD6 is linked to a 2.5 Mbp interval on chromosome 14. MommeD9 is a semi-dominant, homozygous lethal mutation that acts as an enhancer of variegation with respect to the GFP transgene. Mutants have a tendency to become obese as they age, show abnormal haematology profiles, and females develop infertility. MommeD9 is linked to a 17.4 Mbp region on chromosome 7. I produced and studied a strain carrying the same GFP transgene but in a new strain background, C57BL/6J. This strain provided an opportunity to look for strain-specific modifiers of expression of the GFP transgene. Several regions were mapped to chromosomal locations. Further work will be needed to identify the genes involved. This mouse will be useful in future mutagenesis screens of this type.
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Tai, Helen H. "The role of Xist and CHD-1 in gene silencing." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/NQ57070.pdf.
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Dalzell, J. J. "The development of gene silencing strategies for plant parasitic nematodes." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546037.
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Hunter, B. C. "Genetic modifiers of hairpin-induced gene silencing in Arabidopsis thaliana." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604807.
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The Chalcone Synthase (CHS) gene codes for the first step of biosynthesis of the purple pigment anthocyanin. In this study, transgenic Arabidopsis plants with a hairpin construct homologous to part of the CHS coding sequence were used in a genetic screen to identify modifiers of hairpin silencing. Some putative genetic modifiers were identified, but these appear to be the result of transgene:transgene interaction based on shared promoter homology rather than being due to second site suppressors in the Arabidopsis genome. New transgenic Arabidopsis lines were made with hairpin constructs directed to either the promoter or the reading frame of the CHS gene and both types of transgenic showed an anthocyanin-deficient phenotype. For each construct a representative single-insert homozygous transgenic line was selected for subsequent work. Both transgenic lines showed increased methylation of their respective target site and contained short interfering RNA (siRNA) homologous to their target site. A collection of 59 putative modifiers of CHS silencing were tested with both transgenic lines using segregation analysis of the anthocyanin-deficient phenotype in the F2 generation of appropriate crosses. Mutants in AGO4, AGO6, DRD1, DRM2, NRPD2a and NRPE1 act as recessive second site modifiers of the CHS promoter hairpin line phenotype. These mutants are associated with a decrease in DNA methylation at the hairpin target site. Mutant alleles of the DCL4 and HEN1 genes reduce silencing of the CHS coding sequence hairpin. The reduction in silencing is greater in mutants that are hemizygous for the hairpin construct than in those that are homozygous for it. The increase in siRNA in the construct homozygotes, compared to that in the hemizygotes, is perhaps sufficient to overcome any modification of the phenotype by mutants of DCL4 and HEN1.
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Li, Yigen. "Investigations of LIMD1 in miRNA-mediated gene silencing and cancers." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/39756.
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In recent years, LIM domains-containing protein 1 (LIMD1) has been identified as a critical component in microRNA (miRNA)-induced silencing complex (miRISC) to regulate miRNA-mediated gene silencing. Human Argonaute (AGO) 2 with its family members (AGO1-4) are critical for the biogenesis of miRNA and thus miRNA-mediated gene silencing. In this study, we have investigated the direct interaction interfaces between LIMD1 and AGO2. A distinct interface within LIMD1, amino acid (a.a) 140-166, is identified to be responsible for the binding to AGO2 and other members of AGO family. Furthermore, the Linker-2 (L2) domain within AGO2 is identified to be responsible for LIMD1 binding and its dependency on the phosphorylation at serine 387 (S387) residue within the L2 domain of AGO2. The phospho-mimic mutant (S387E) enhances the binding of AGO2 to LIMD1, whereas the phospho-deficient mutant (S387A) attenuates AGO2-LIMD1 interaction. In addition, the association of LIMD1 with other AGOs is also dependent on the phosphorylation at the equivalent conserved serine residue within the L2 domain on other AGOs. In addition to the above aspects, LIMD1 is a tumour suppressor gene frequently down-regulated in more than 75% human lung tumours. Because of their loss of expressions or functions, it is of the inherent difficulty in targeting tumour suppressor genes to treat cancers. In this study, the concept of synthetic lethality was used to identify possible protein kinases, the ablation of which are synthetically lethal to LIMD1 negative cancer cell lines. As a result, drugs that target these kinases may represent novel targeted therapies for LIMD1 negative lung tumours. ACVR2B and STK39 are validated to be synthetically lethal with LIMD1 loss. Additionally, the complete loss of LIMD1 expression causes a dramatic increase of STK39 expression due to miRNA-mediated gene silencing pathway. The inverse relationship between LIMD1 and STK39 may represent a conserved and fundamental signalling response and may be a predictive marker for STK39-targeted therapy.
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Debacker, Alexandre J. "Improving gene silencing oligonucleotides by incorporation of peptide nucleic acids." Thesis, University of Southampton, 2017. https://eprints.soton.ac.uk/422159/.
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The use of PNAs in therapeutics is limited by its mechanism of action. PNA (peptide nucleic acid) acts as steric blocker and therefore one copy per target of these therapeutic oligonucleotides is needed. While this mechanism is very interesting in splice-switching therapeutics it falls short of Ago2 or RNase H dependent gene silencing. Although the failure of PNA to recruit these enzymes to cleave their target could be a deal breaker, the high nuclease stability, neutral backbone and high affinity of PNAs are features that could enhance efficacy of siRNAs and antisense oligonucleotides (ASOs). First, the present work discussed the design, synthesis and properties of PNAs and LNA-modified oligonucleotides, which were used to switch off a silencing modified small non-coding RNA MicAstab. Then, usage of PNAs in tandem with highly modified siRNA is discussed. The silencing activity of siRNAs containing PNA sense strand as RNA:PNA duplex was investigated. Association of PNA and siRNA was further studied and silencing activity and biophysical properties of PNA-Peptide carrier for siRNA delivery is shown. Finally, the optimisation of DNA-PNA chimeras was investigated. The synthesis of the monomers as well as the oligomerisation of LNA-DNA-PNA is described. The biophysical properties of chimeras and their ability to efficiently knock down MALAT1 RNA in cells are shown in this thesis.
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George, Gavin M. (Gavin Mager). "Virus induced gene silencing for the study of starch metabolism." Thesis, Stellenbosch : University of Stellenbosch, 2010. http://hdl.handle.net/10019.1/4024.
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Thesis (PhD (Plant Biotechnology))--University of Stellenbosch, 2010.ENGLISH ABSTRACT: Virus Induced Gene Silencing (VIGS) was optimized to allow for the study of starch metabolism. The plastidial inorganic pyrophosphatase gene, for which a mutant has never been identified, was studied using VIGS and it was found to have a broad role in this subcellular compartment. The accumulation of inorganic pyrophosphate limited the production of starch, carotenoids, chlorophyll, and increased the plants susceptibility to drought stress. These effects highlight the importance of this enzyme in maintaining a low intraplastidial concentration of PPi providing an environment which facilitates these anabolic processes. Several genes involved in starch synthesis and degradation were also targeted with the aim of establishing a system of multiple gene silencing for the study of metabolic pathways. One, two and three genes were successfully silenced using this system which was validated based on previously published data. Interestingly, simultaneous silencing of the two isoforms of disproportionating enzyme led to a novel phenotype as a large reduction in starch instead of the expected increase was observed.
No Afrikaans abstract available
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Marr, Edward John. "RNA interference (RNAi) for selective gene silencing in Astigmatid mites." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25722.
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Psoroptic mange, caused by the Astigmatid mite Psoroptes ovis, is an ectoparasitic disease of significant economic importance to agriculture on a global scale and poses a serious welfare concern. With the current chemotherapeutic controls considered unsustainable, there is pressing need for novel control strategies. RNA interference has been proposed as a potential high throughput approach for the identification of novel therapeutic targets with high specificity, speed and at a relatively low cost compared to the existing methods. The presence of the components of the RNA interference (RNAi) pathway in P. ovis was first confirmed through in silico analyses of the P. ovis transcriptome and, following development of a non-invasive immersion method of double stranded RNA (dsRNA) delivery, gene silencing by RNAi was demonstrated in P. ovis. Statistically-significant reduction of transcript level was measured for the three genes targeted: P. ovis mite group 2 allergen (Pso o 2), P. ovis mu class glutathione S-transferase (PoGST-mu1) and P. ovis beta tubulin (Poβtub). This is the first demonstration of gene silencing by RNAi in P. ovis and provides a key mechanism for mining transcriptomic and genomic datasets in the future for novel targets of intervention against P. ovis. The first assessment of gene silencing was also performed in two related Astigmatid mites of high medical importance; the European house dust mite Dermatophagoides pteronyssinus and the scabies mite Sarcoptes scabiei. A statistically-significant reduction in expression of a D. pteronyssinus mu class glutathione S-transferase (DpGST-mu1) transcript was observed. No significant reduction in expression of a S. scabiei mu class glutathione S-transferase (SsGST-mu1) transcript was observed. Additionally, microRNAs (miRNAs) from the related miRNA pathway were identified in a P. ovis small RNA sample and were sequenced and annotated.
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Torrea, Muguerza Natalia Isabel. "Role of LSH in the establishment of epigenetic gene silencing." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31546.
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DNA methylation is essential for mammalian development and transcriptional repression of genes and retrotransposons during embryo development and in somatic cells. The patterns of DNA methylation are established by de novo DNA methyltransferases, which are regulated by developmental signalling and require access to chromatin. Besides DNA methyltransferases, other proteins have recently been implicated in DNA methylation, such as the ATP-dependent chromatin remodeler LSH. The absence of LSH in mouse embryos leads to defects in DNA methylation and development. In relation to this, mutations in LSH have been found to cause Immunodeficiency-Centromeric instability-Facial anomalies (ICF) syndrome. This syndrome is characterized by centromeric instability and CpG hypomethylation of centromeric satellite repeats, and is most often caused by mutations in the catalytic domain of the DNA methyltransferase DNMT3B. LSH is essential for developmentally programmed de novo DNA methylation of large chromosomal domains including promoters of protein coding genes and repetitive sequences. Importantly, fibroblasts derived from chromatin remodeling ATPase LSH-null mouse embryos, which lack DNA methylation at transposons and specific gene promoters, are capable of re-establishing normal patterns of DNA methylation and transcriptional silencing of misregulated genes upon re-expression of LSH. The ATP hydrolysis by LSH is essential for its function in gene silencing and de novo DNA methylation. However, the molecular mechanisms of LSH-dependent gene silencing and de novo DNA methylation are yet unclear. Here we use an inducible system that enables controlled expression of LSH in Lsh-null mouse embryonic fibroblasts (MEFs) to follow chromatin dynamics, transcriptional silencing and establishment of de novo DNA methylation. This conditionally reversible Lsh knockout cellular system allowed us to study the order of events occurring immediately after LSH restoration in MEF cell lines in order to elucidate the molecular mechanism of LSH-dependent gene silencing. We have demonstrated that LSH upon its restoration localises to the promoters of LSH-dependent loci leading to a mild decrease in the occupancy of H3, which reinforces the previously shown role of LSH as a chromatin remodeler. Simultaneously, there is removal of acetyl groups from H3 tails when LSH is bound to these target regions, which might be facilitated by the interaction of HDACs with LSH. The removal of H3Ac marks is followed by deposition of H3K9me2 by G9a/GLP histone methylases at the same time point when misregulated genes are silenced. This suggests that LSH creates a suitable substrate for G9a/GLP promoting gene silencing. Surprisingly, transcriptional repression occurs without acquisition of DNA methylation at the promoters of these loci. This order of events implies that LSH plays a role as a chromatin remodeler leading to changes in chromatin structure and modifications that facilitate epigenetic gene silencing without DNA methylation in the initial period when LSH is restored in MEF cell lines. Furthermore, deposition of H3K9me2 by the G9a/GLP complex is critical for silencing of specific genes, but not for repetitive elements such as IAPs. The histone modification H3K27me3 seems to play a transitory role in the silencing of IAP retrotransposons in the absence of G9a/GLP activity. In conclusion, this work has demonstrated that changes in chromatin modifications leading to a transcriptionally repressive chromatin state can be established in somatic cells by the chromatin remodeler LSH without acquisition of DNA methylation. This suggests that the primary role of LSH is to promote changes in chromatin structure and modifications that lead to gene silencing and not DNA methylation, which most likely occurs as a consequence of transcriptional silencing.
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Almeida, Carina Marisa dos Santos. "Gold nanoparticle-DNA conjugates for oligonucleotide vectorization towards gene silencing." Master's thesis, Faculdade de Ciências e Tecnologia, 2011. http://hdl.handle.net/10362/6212.
Full textAbstract:
Dissertação para obtenção do Grau de Mestre em
Genética Molecular e BiomedicinaThe main objective of the work presented in this thesis was to develop a gene silencing system by taking advantage of the nanovectorization capability and optical properties of gold nanoparticles. The idea is based on the construction of a DNA structure containing a therapeutic oligonucleotide with the ability to form Hoogsteen hydrogen bonds with double-stranded DNA, producing a DNA triple helix, besides silencing the gene of interest. Hoogsteen bonds, more unstable than the conventional Watson-Crick bonds, permit the achievement of lower melting temperatures. This attribute, coupled with the ability to generate heat by laser irradiation of the gold nanoparticles used, will allow the release of the therapeutic oligonucleotide and subsequent gene silencing without significant increase in the medium’s temperature. Thus, the thesis comprises three major sections: structure design and formation, vectorization, and gene expression silencing; the tasks involved in each of these sections were conducted in parallel. The design of the obtained structure took into account the desired melting temperature, stability at physiological conditions of the sequence-forming nucleotides, the number of Hoogsteen bonds and ionic conditions. To evaluate the formation of this structure, spectroscopic techniques were mainly used: FRET analysis and ultraviolet melting curves. Both approaches allowed the identification of interactions in the presence of therapeutic oligonucleotide compared with its absence, which may indicate structure formation. In addition, melting curves allowed the determination of the temperature of release of this oligonucleotide – 40ºC. The double-stranded DNA functionalization to gold nanoparticles has been achieved, but there was no difference in electrophoretic migration when the three oligonucleotides were present. However, the therapeutic oligonucleotide was able to efficiently inhibit gene expression in in vitro transcription and translation assays with efficiency up to 95% and 60% respectively.
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Bruxner, Timothy James. "Characterisation of mutants influencing epigenetic gene silencing in the mouse." Thesis, The University of Sydney, 2007. http://hdl.handle.net/2123/2238.
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The field of epigenetics emerged primarily from studies in Drosophila, and is now being studied intensively by mammalian biologists. In order to increase our knowledge of epigenetic gene control in the mouse, I have studied modifiers of epigenetic gene silencing. My main method of investigation involved the characterisation of mutants from a sensitised ENU mutagenesis screen performed previously in our laboratory. The screen was carried out in an FVB/NJ strain carrying a variegating GFP transgene expressed in erythrocytes. To date we have recovered 12 dominant (D) and seven recessive (R) mutant mouse lines from this screen that display altered transgene expression. We have named these Mommes (Modifiers of murine metastable epialleles). I investigated the phenotype and attempted to identify the underlying causative mutation of two of these Momme mutants. MommeD6 is a semi-dominant, homozygous lethal mutation that acts as a suppressor of variegation with respect to the GFP transgene. This mutation has a large effect on the level of expression of the transgene in expressing cells, but little effect on the percentage of cells expressing the transgene. MommeD6 is linked to a 2.5 Mbp interval on chromosome 14. MommeD9 is a semi-dominant, homozygous lethal mutation that acts as an enhancer of variegation with respect to the GFP transgene. Mutants have a tendency to become obese as they age, show abnormal haematology profiles, and females develop infertility. MommeD9 is linked to a 17.4 Mbp region on chromosome 7. I produced and studied a strain carrying the same GFP transgene but in a new strain background, C57BL/6J. This strain provided an opportunity to look for strain-specific modifiers of expression of the GFP transgene. Several regions were mapped to chromosomal locations. Further work will be needed to identify the genes involved. This mouse will be useful in future mutagenesis screens of this type.
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Arooj, Mahira. "Precision Genome Engineering and Gene Silencing Using CRISPR/dCas9 System." Thesis, Curtin University, 2018. http://hdl.handle.net/20.500.11937/73571.
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This research aimed to repress target genes by modulating their expression through rewriting of aberrant epigenetic landscapes, including DNA methylation and histone post-translational modifications, utilizing epigenetic repressor domains. The epigenetic repressor domains included KRAB, DNMT3A, UHRF1 and CSD, which were delivered via the epigenetic editing tools ZFs, TALEs and the CRISPR/dCas9 system. Our findings suggest that a combination of multiple epigenetic repressor domains targeting epigenetic marks involved in epigenetic cross-talk significantly repressed target genes.
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Vickaryous, Nicola. "An ENU mutagenesis screen to identify modifiers of gene silencing in the mouse." Thesis, The University of Sydney, 2005. https://hdl.handle.net/2123/28042.
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There is increasing evidence that the epigenotype of an organism contributes to phenotype. With the aim of understanding more about the factors involved in the initiation, maintenance and reprogramming of epigenetic state, our laboratory has designed an ENU mutagenesis screen to recover modifiers of gene silencing in the mouse. In this thesis I describe the dominant and recessive screens 1 performed which recovered a total of nine mutant lines which showed alterations in gene silencing, some of these lines had increased transgene expression (suppressors of variegation), and others had decreased transgene expression (enhancers of variegation). These mutant lines were able to modify gene silencing at a variegating transgene and were therefore named Modifiers of murine metastable epialleles (Mommes). I worked extensively with three dominant lines recovered from this and a previously performed, identical screen; Momme D4, Momme D5 and Momme D7. The mutations underlying all three of these lines were mapped to discrete genomic regions and in the case of Momme D4, a mutation was found in the Snf2h gene, which encodes a compenent of chromatin remodelling complexes. The three dominant lines examined all displayed dose—dependent effects, in all cases homozgyosity for the mutations was lethal. Stochastic effects on viability were also found in association with heterozygosity for the mutations. Two of the mutant lines, Momme D4 and Momme D7 affected expression at a single copy endogenous allele known to be sensitive to epigenetic state, agouti viable yellow, A”. Breeding studies have revealed that these mutations display unusual maternal and paternal effects, whereby wildtype offspring of heterozygous parents are affected. One of the recessive mutant lines, Momme R1, was studied at some depth. Age-associated loss of fertility and susceptibility to development of ovarian teratomas was seen in homozygous females. A mutation was identified in the Foxo3a gene of the mutant mice, this gene encodes a
transcription factor with roles in cell cycle control, apoptosis and DNA repair. The mechanism by which loss of Foxo3a affects transgene silencing is not clear and these mice provide a platform to investigate this further. In summary, several mouse models have been produced which represent mutations that alter gene silencing in the mouse. By studying the behaviour of these mutant colonies l have found evidence that the untransmitted genotype of the parent can influence the phenotype of the offspring.
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Popova, Blagovesta. "HelF, a suppressor of RNAi mediated gene silencing in Dictyostelium discoideum." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=980955947.
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Chau, Ling Bess. "Capacity of plant-derived siRNA for gene silencing in mammalian cells." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B36778874.
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Abdel, Rahim Ma'en Ahmad. "Gene silencing in cancer cells using siRNA : genetic and functional studies." Diss., Texas A&M University, 2004. http://hdl.handle.net/1969.1/218.
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Sequence-specific small interfering RNA (siRNA) duplexes can be used for gene silencing in mammalian cells and as mechanistic probes for determining gene function. Transfection of siRNA for specificity protein 1 (Sp1) in MCF-7 or ZR-75 cells decreased Sp1 protein in nuclear extracts, and immunohistochemical analysis showed that Sp1 protein in transfected MCF-7 cells was barely detectable. Decreased Sp1 protein in MCF-7 was accompanied by a decrease in basal and estrogen-induced transactivation and cell cycle progression. These results clearly demonstrate the key role of Sp1 protein in regulating growth and gene expression of breast cancer cells. The aryl hydrocarbon (AhR) is a ligand-activated nuclear transcription factor. siRNA for the AhR decreased TCDD-induced CYP1A1 protein, CYP1A1dependent activity, and luciferase activity in cells transfected with an Ah-responsive construct. 17β-Estradiol (E2) induces proliferation of MCF-7 cells, and this response is inhibited in cells cotreated with E2 plus TCDD. The effects of TCDD on E2-induced cell cycle progression were partially blocked in MCF-7 cells transfected with siRNA for AhR. The decrease in AhR protein in MCF-7 cells was also accompanied by increased G0/G1 → S phase progression. Surprisingly, TCDD alone induced G0/G1 → S phase progression and exhibited estrogenic activity in MCF-7 cells transfected with siRNA for the AhR. In contrast, degradation of the AhR in HepG2 liver cancer cells resulted in decreased G0/G1 → S phase progression, and this was accompanied by decreased expression of cyclin D1, cyclin E, cdk2 and cdk4. In the absence of ligand, the AhR exhibits growth inhibitory (MCF-7) and growth promoting (HepG2) activity that is cell context-dependent. Sp family proteins play a complex role in regulation of pancreatic cancer cells growth and expression of genes required for growth, angiogenesis and apoptosis. Sp1, Sp3 and Sp4 cooperatively activate VEGF promoter constructs in these cells; however, only Sp3 regulates cell proliferation. siRNA for Sp3 inhibits phosphorylation of retinoblastoma protein, blocks G0/G1 → S phase progression of Panc-1 cells, and upregulates p27 protein/promoter activity. Thus, Sp3 plays a critical role in angiogenesis (VEGF upregulation) and the proliferation of Panc-1 cells by a novel mechanism of Sp3-dependent suppression of the cyclin-dependent kinase inhibitor p27.