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Abstract The RAS family genes encode small GTP-binding cytoplasmic proteins that are important signaling molecules. They regulate cell growth, survival and differentiation by coupling receptor activation to downstream effector pathways. Activating mutations of oncogenic RAS pathway genes are frequently detected in human cancers. The role of KRAS in tumor formation is not questionable. It’s implication in tumor maintenance is less well validated. The KRAS dependency is a key question to answer before to develop KRAS inhibitor. Targeted genome editing using CRISPR/Cas9 is a relatively new, revolutionary technology allowing for efficient and directed alterations of the genome. CRISPR is a genome-editing platform that makes use of the bacterially-derived endonuclease Cas9 to introduce DNA double-strand breaks at precise locations in the genome using complementary guide RNAs. These double strand breaks can be repaired by homologous recombination DNA repair mechanisms thank to a donor DNA template. By this way mutations can be introduced at desired loci, DNA fragment can be deleted or introduce at the desired location. We aimed at investigating the KRAS dependence and we applied the CRISPR-Cas9 technology to engineer isogenic cancer cells harboring a “conditional KRAS gene knockout" by exchanging the KRAS endogenous promoter. This promoter replacement approach can be used also to validate new targets. Citation Format: Christophe Marcireau, Fréderic Lacroix, Dietmar Hoffmann, May Cindhuchao, Loreley Calvet, Yvette Ruffin, Laurent Debussche. KRAS dependency, a gene editing approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1673.
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Tsai, Kun-Che, Shin-Yu Fang, Shu-Jyuan Yang, Ming-Jium Shieh, Win-Li Lin, and Wen-Shiang Chen. "Time dependency of ultrasound-facilitated gene transfection." Journal of Gene Medicine 11, no. 8 (August 2009): 729–36. http://dx.doi.org/10.1002/jgm.1347.
Croce, Carlo M. "miRNAs in the spotlight: Understanding cancer gene dependency." Nature Medicine 17, no. 8 (August 2011): 935–36. http://dx.doi.org/10.1038/nm0811-935.
Zhang, Qing, Xiaodan Fan, Yejun Wang, Mingan Sun, Samuel S. M. Sun, and Dianjing Guo. "A Model-Based Method for Gene Dependency Measurement." PLoS ONE 7, no. 7 (July 19, 2012): e40918. http://dx.doi.org/10.1371/journal.pone.0040918.
Gao, Xin, Daniel Q. Pu, and Peter X. K. Song. "Transition Dependency: A Gene-Gene Interaction Measure for Times Series Microarray Data." EURASIP Journal on Bioinformatics and Systems Biology 2009 (2009): 1–12. http://dx.doi.org/10.1155/2009/535869.
Li, Zhong, and Zhou. "Prediction of Bone Metastasis in Breast Cancer Based on Minimal Driver Gene Set in Gene Dependency Network." Genes 10, no. 6 (June 17, 2019): 466. http://dx.doi.org/10.3390/genes10060466.
Bone is the most frequent organ for breast cancer metastasis, and thus it is essential to predict the bone metastasis of breast cancer. In our work, we constructed a gene dependency network based on the hypothesis that the relation between one gene and the risk of bone metastasis might be affected by another gene. Then, based on the structure controllability theory, we mined the driver gene set which can control the whole network in the gene dependency network, and the signature genes were selected from them. Survival analysis showed that the signature could distinguish the bone metastasis risks of cancer patients in the test data set and independent data set. Besides, we used the signature genes to construct a centroid classifier. The results showed that our method is effective and performed better than published methods.
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Zhou, Xiangdong, Keith C. C. Chan, Zhihua Huang, and Jingbin Wang. "Determining dependency and redundancy for identifying gene–gene interaction associated with complex disease." Journal of Bioinformatics and Computational Biology 18, no. 05 (October 2020): 2050035. http://dx.doi.org/10.1142/s0219720020500353.
As interactions among genetic variants in different genes can be an important factor for predicting complex diseases, many computational methods have been proposed to detect if a particular set of genes has interaction with a particular complex disease. However, even though many such methods have been shown to be useful, they can be made more effective if the properties of gene–gene interactions can be better understood. Towards this goal, we have attempted to uncover patterns in gene–gene interactions and the patterns reveal an interesting property that can be reflected in an inequality that describes the relationship between two genotype variables and a disease-status variable. We show, in this paper, that this inequality can be generalized to [Formula: see text] genotype variables. Based on this inequality, we establish a conditional independence and redundancy (CIR)-based definition of gene–gene interaction and the concept of an interaction group. From these new definitions, a novel measure of gene–gene interaction is then derived. We discuss the properties of these concepts and explain how they can be used in a novel algorithm to detect high-order gene–gene interactions. Experimental results using both simulated and real datasets show that the proposed method can be very promising.
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Ding, Yunfeng, Luis E. Contreras-Llano, Eliza Morris, Michelle Mao, and Cheemeng Tan. "Minimizing Context Dependency of Gene Networks Using Artificial Cells." ACS Applied Materials & Interfaces 10, no. 36 (August 16, 2018): 30137–46. http://dx.doi.org/10.1021/acsami.8b10029.
The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations, and fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here, we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy-number genomic amplifications generate multiple collateral dependencies within the amplified region in most cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency led to the identification of genes, the expression of which may constitute predictive biomarkers of dependency. In conclusion, our study provides a set of druggable targets specific for each amplification, opening the possibility to specifically target amplified tumors on this basis.
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Grzywacz, Anna, Wojciech Barczak, Jolanta Chmielowiec, Krzysztof Chmielowiec, Aleksandra Suchanecka, Grzegorz Trybek, Jolanta Masiak, Paweł Jagielski, Katarzyna Grocholewicz, and Blazej Rubiś. "Contribution of Dopamine Transporter Gene Methylation Status to Cannabis Dependency." Brain Sciences 10, no. 6 (June 23, 2020): 400. http://dx.doi.org/10.3390/brainsci10060400.
The susceptibility to cannabis dependency results from the influence of numerous factors such as social, genetic, as well as epigenetic factors. Many studies have attempted to discover a molecular basis for this disease. However, our study aimed at evaluating the connection between altered methylation of the dopamine transporter gene (DAT1) promoter CpG sites and cannabis dependency. In the cases of some DNA sequences, including the DAT1 gene region, their methylation status in blood cells may reflect a systemic modulation in the whole organism. Consequently, we isolated the DNA from the peripheral blood cells from a group of 201 cannabis-dependent patients and 285 controls who were healthy volunteers and who were matched for age and sex. The DNA was subjected to bisulfite conversion and sequencing. Our analysis revealed no statistical differences in the general methylation status of the DAT1 gene promoter CpG island between the patients and controls. Yet, the analysis of individual CpG sites where methylation occurred indicated significant differences. These sites are known to be bound by transcription factors (e.g., SP1, p53, PAX5, or GR), which, apart from other functions, were shown to play a role in the development of the nervous system. Therefore, DAT1 gene promoter methylation studies may provide important insight into the mechanism of cannabis dependency.
Lazaridis, Konstantinos. "Investigation of the Smad-dependency for protease and inhibitor gene expression in response to TGF-β1." Thesis, University of East Anglia, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410505.
Huang, Alice. "Calcium-sensing Receptor Mediated Control of CYP27B1 Promoter-dependent Gene & Protein Expression: Complex Extracellular Ca2+ Concentration Dependence." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20127.
Changes in extracellular Ca2+ (Ca2+o) differentially modulate 25-hydroxyvitamin D3 1α-hydroxylase (1αOHase; encoded by CYP27B1) mRNA and protein levels in cell types including the renal proximal tubule (inhibitory), parathyroid, and skeletal osteoblasts (stimulatory) to control 1,25-dihydroxyvitamin D3 synthesis. We hypothesised that the calcium-sensing receptor (CaSR) mediated Ca2+o concentration-dependent control of 1αOHase, either directly through Ca2+o, or through the local production of parathyroid hormone related peptide (PTHrP). To investigate promoter activity, I transfected a firefly luciferase reporter gene under the control of the 1501 bp human CYP27B1 promoter into HEK-293 cells that stably expressed the CaSR (HEK-CaSR cells) and measured luciferase activities from cells exposed to various Ca2+o concentrations. CYP27B1 promoter-controlled luciferase expression exhibited a biphasic Ca2+o-dependent response in luciferase activity and protein that peaked with a 2-fold increase from basal levels at around 3.0 mM Ca2+o in HEK-CaSR cells. This response was absent in HEK-293 cells and was shifted to the left or right in the presence of the CaSR positive allosteric modulator, cinacalcet, or negative allosteric modulator, NPS-2143, respectively, indicating that both the stimulatory and inhibitory phases were CaSR-mediated. Firefly luciferase and 1αOHase mRNA levels obtained from quantitative RT-PCR exhibited a monophasic Ca2+o-dependent increase and suggests that the stimulatory phase arises from increased mRNA expression, whereas the inhibitory phase arises from reduced protein levels. Inhibitor and mutational studies suggested that the stimulatory phase was dependent on Gq/11 signalling, whereas the inhibitory phase requires MEK and PKC-dependent phosphorylation of the crucial T888 site of the CaSR's C-terminal tail.
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Tronnersjö, Susanna. "Functional studies of RNA polymerase II-dependent transcription in yeast Saccharomyces cerevisiae /." Uppsala : Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, 2006. http://epsilon.slu.se/2006109.pdf.
Lori, Toju William Peter. "Ca²⁺-dependent gene expression and epilepsy." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613662.
Johansson, Anna. "Dependence-induced changes in opioid-receptor gene expression." Thesis, Linköpings universitet, Institutionen för fysik, kemi och biologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-90034.
Using drugs such as alcohol and morphine among others can be addictive in some individuals, and progress into a substance abuse disorder. The mesolimbic dopaminergic system (MD-system) is involved in the reward process during the development of drug addiction. The MD-system is critical for survival and affects different behaviors in both man and animal. Neurochemical pathways drive for instance physical activity, food intake, love and reproduction and are part of the natural reward process involved partly in the release of dopamine (DA) into frontal lobes. Within the MD-system opioid receptors throughout the brain are affected by drug intake, and activation of these receptors modulate DA-release in brain regions involved in reward-behavior. The aim of this study was to evaluate gene expression of MOR and DOR within the endogenous opioid system (EO-system) in relation to voluntary physical activity, a natural reinforcer. Further on investigations of the drug alcohol was compared to the natural reinforcer sucrose using voluntary consumption. For both experiments qRT-PCR was used to measure mRNA levels of MOR and DOR from brain areas of interest. We found a small significant up regulation in NAc, PFC and VTA but for DOR in VTA a down regulation in gene expression of physical exercising mice. Additionally these two different genes OPRM1- and the OPRD1- gene are down regulated in VTA and NAc due to alcohol- and sugar-intake. This implicate that the natural reward system and their ORs point in the direction of earlier findings; the opioid receptors have a key role in regulate alcohol intake and the natural rewarding stimuli as food intake.
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He, Jie. "Isolation of An ARGONAUTE Gene in Pelargonium and Identification Of Candidate Genes Regulated Through ARGONAUTE4-Dependent RNA-Dependent DNA Methylation In Arabidopsis." Connect to full text in OhioLINK ETD Center, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=toledo1260812913.
Dissertation (Ph.D.)--University of Toledo, 2009. Typescript. "Submitted as partial fulfillment of the requirements for the Doctor of Philosophy degree in Biology." Bibliography: leaves 54-56, 91-95, 118-119, 133-139.
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Lin, Jialiang. "Cordycepin affects growth factor-dependent gene expression." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/50823/.
The natural compound cordycepin (3’-deoxyadenosine) causes a reduction in breast cancer cell viability. Microarray analysis showed that growth related genes are down-regulated by cordycepin. Indeed, mTOR, ERK and AMPK signalling was shown to be altered by cordycepin, but the effect was too fast to be mediated by transcriptional changes. It was hypothesised that cordycepin affected signal transduction through translation. However, polysome profiling did not identify clear candidates for the effects of cordycepin on signal transduction but unveiled that cordycepin leads to translation repression on 5’ terminal oligopyrimidine (TOP) mRNAs. As TOP mRNAs are known to be regulated by mTOR signaling, this result consistently suggests mTOR signaling is inhibited by cordycepin treatment. To test if it is possible that cordycepin affects gene expression via signal transduction, we compared its effects to various signal transduction inhibitors and an activator. So far, Pictilisib, a pan-PI3K inhibitor, is the only inhibitor that mimics both the gene expression and signal transduction effects of cordycepin, indicating the PI3K-PDK1-AKT axis is affected by cordycepin. The RNAs upregulated by cordycepin were highly enriched in a group of non-coding RNAs, which are also appeared to induce during serum withdrawal. Knockdown of poly(A) polymerases induced these RNAs, indicating that they probably are degraded by the PABPN1 and poly(A) polymerase dependent nuclear RNA decay pathway. Thus the data suggest that cordycepin affects gene regulation by two distinct pathways, one affecting signal transduction and growth related mRNA expression and another affecting polyadenylation mediated decay of non-coding mRNAs.
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Farris, Sean. "Myelin Gene Expression: Implications for Alcohol Abuse and Dependence." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/322.
Acute behavioral responses to ethanol have predictive value for determining an individual's risk of long-term drinking behavior. Although the neurobiology of alcohol abuse is complex, prior studies from our laboratory demonstrated differential myelin-associated gene expression (MAGE) in medial prefrontal cortex (PFC) as one potential mechanism influencing acute ethanol behaviors between C57BL/6J (B6) and DBA/2J (D2) mice. Our laboratory and others have also shown MAGE is reduced in PFC of alcoholics. Herein, I have extended these findings through expression profiling of PFC into chronic models of ethanol self-administration from non-human primates and mice. Together, these results suggest that regulation of MAGE may be relevant to behavioral phenotypes witnessed in alcoholism. The pathogenesis of alcoholism progresses through multiple stages of drug exposure and withdrawal, however, genetic predisposition is also a major contributing factor for this disease. Therefore, I tested the hypothesis that not only does ethanol have direct effects on MAGE, but also variation in basal MAGE within the PFC is a molecular endophenotype underlying ethanol behavioral sensitivity. Bioinformatics of basal MAGE across the BXD recombinant inbred panel (n=29), derived from B6 and D2 mice, revealed a densely correlated myelin gene network associated with several ethanol behavioral phenotypes. Literature association tools identified Fyn kinase as potential regulator of MAGE. Fyn knockout mice are known to be more sensitive to the sedative-hypnotic properties of ethanol in the loss of righting reflex (LORR) paradigm. Microarray analysis of Fyn knockout mice revealed a significant decrease in MAGE, suggesting MAGE may be an underlying factor for LORR. In support of this premise, microarray analysis of genetic variance in LORR across Inbred Long Sleep and Inbred Short Sleep mice, as well as congenics for the Lore5 quantitative trait locus, also demonstrated an inverse relationship between MAGE and duration of LORR. The hypothesis was further investigated using cuprizone to model demyelination in B6 mice and test them in a battery of acute ethanol behaviors. Cuprizone-treated mice had a significantly greater duration in LORR (p < 0.01), demonstrating that myelin is an important contributor to the genetic variance in LORR. Thus, through genetic, genomic, and pharmacological tools I have ‘molecularly triangulated’ a myelin gene network as a contributing factor influencing acute ethanol behavioral sensitivity. The ability of myelin to alter acute ethanol sensitivity may warrant a prospective study of myelin in humans as a predictive molecular phenotype for an individual’s risk of developing alcohol dependence. Additionally, further genomic dissection of MAGE architecture and associated networks may aid in developing novel pharmacotherapies for an alcohol use disorder. Supported by NIAAA grants F31 AA018615 to SPF
Azmi, Peter B. Bacterially-derived DNA elements from the gene GPT can block enhancer-dependent transcriptional activation of an adjacent gene in a position-dependent manner. Ottawa: National Library of Canada, 2002.
D, Takezawa, and United States. National Aeronautics and Space Administration., eds. Calcium-dependent protein kinase genes in corn roots. [Washington, DC: National Aeronautics and Space Administration, 1996.
D, Takezawa, and United States. National Aeronautics and Space Administration., eds. Calcium-dependent protein kinase genes in corn roots. [Washington, DC: National Aeronautics and Space Administration, 1996.
D, Takezawa, and United States. National Aeronautics and Space Administration., eds. Calcium-dependent protein kinase genes in corn roots. [Washington, DC: National Aeronautics and Space Administration, 1996.
Lightfoot, Maria Eugenia Vidal. Studies of the calcium dependence of prolactin gene expression in GH[inferior]3 cells. Birmingham: University of Birmingham, 1990.
Sprowl, Jason A. Identification of PKCa-dependent genes associated with growth arrest in Saccharomyces cerevisiae. Sudbury, Ont: Laurentian University, 2004.
D, Takezawa, Poovaiah B. W, and United States. National Aeronautics and Space Administration., eds. Chimeric plant calcium/calmodulin-dependent protein kinase gene with a neural visinin-like calcium-binding domain. [Washington, DC: National Aeronautics and Space Administration, 1995.
Chetty, Girija, and Madhu Chetty. "Multiclass Microarray Gene Expression Analysis Based on Mutual Dependency Models." In Pattern Recognition in Bioinformatics, 46–55. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-642-04031-3_5.
Mallick, Partho, Oindrila Ghosh, Priyanka Seth, and Anupam Ghosh. "Kohonen’s Self-organizing Map Optimizing Prediction of Gene Dependency for Cancer Mediating Biomarkers." In Advances in Intelligent Systems and Computing, 863–70. Singapore: Springer Singapore, 2018. http://dx.doi.org/10.1007/978-981-13-1501-5_75.
Salnikow, Konstantin, and Kazimierz S. Kasprzak. "Nickel-Dependent Gene Expression." In Nickel and Its Surprising Impact in Nature, 581–618. Chichester, UK: John Wiley & Sons, Ltd, 2007. http://dx.doi.org/10.1002/9780470028131.ch16.
Diamond, Scott L., and Larry V. Mcintire. "Gene Regulation in Endothelial Cells." In Flow-Dependent Regulation of Vascular Function, 62–84. New York, NY: Springer New York, 1995. http://dx.doi.org/10.1007/978-1-4614-7527-9_4.
Spížek, J., P. Ryšavý, M. Klégr, J. Náprstek, J. Janećek, and P. Tichý. "DNA-Dependent RNA Polymerase from Streptomyces Granaticolor." In Gene Manipulation and Expression, 196–208. Dordrecht: Springer Netherlands, 1985. http://dx.doi.org/10.1007/978-94-011-6565-5_15.
Cunningham, John T., Michael Pourdehnad, Craig R. Stumpf, and Davide Ruggero. "Investigating Myc-Dependent Translational Regulation in Normal and Cancer Cells." In The Myc Gene, 201–12. Totowa, NJ: Humana Press, 2013. http://dx.doi.org/10.1007/978-1-62703-429-6_13.
Kovalski, Joanna R., Yichen Xu, and Davide Ruggero. "Examining Myc-Dependent Translation Changes in Cellular Homeostasis and Cancer." In The Myc Gene, 255–66. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1476-1_13.
Brunetti-Pierri, Nicola, and Philip Ng. "Helper-dependent adenoviral vectors." In Gene Therapy for Autoimmune and Inflammatory Diseases, 193–207. Basel: Springer Basel, 2010. http://dx.doi.org/10.1007/978-3-0346-0165-8_13.
Flores, Enrique, Alicia M. Muro-Pastor, and Antonia Herrero. "Cyanobacterial Nitrogen Assimilation Genes and NtcA-Dependent Control of Gene Expression." In The Phototrophic Prokaryotes, 463–77. Boston, MA: Springer US, 1999. http://dx.doi.org/10.1007/978-1-4615-4827-0_54.
Fabris, Fabio, and Alex A. Freitas. "Dependency network methods for Hierarchical Multi-label Classification of gene functions." In 2014 IEEE Symposium on Computational Intelligence and Data Mining (CIDM). IEEE, 2014. http://dx.doi.org/10.1109/cidm.2014.7008674.
Dry, Jonathan R., Darren Hodgson, Roz Brant, Tom Liptrot, Elizabeth Harrington, Carl Barrett, and Paul D. Smith. "Abstract A209: Predicting genetic drivers of MEK dependency with gene expression." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-a209.
Sefidmazgi, Ali Gorji, Fatemeh Ahmadi-Abkenari, and Seid Abolghasem Mirroshandel. "Correlation analysis as a dependency measures for inferring of time-lagged gene regulatory network." In 2016 Eighth International Conference on Information and Knowledge Technology (IKT). IEEE, 2016. http://dx.doi.org/10.1109/ikt.2016.7777761.
Yeerna, Huwate, Ramya Rangan, Andrew Aguirre, William Kim, Francisca Vazquez, Barbara Weir, Mahmoud Ghandi, et al. "Abstract 1555: Pan-cancer patterns of synthetic lethality: statistical modeling of gene dependency profiles." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1555.
Weekes, Daniel, Elodie Noel, Callum Walker, Nick Balan, Vandna Shah, Bhavna Sidhu, Anna Pardix, et al. "Abstract 3363:PUM3is a triple-negative breast cancer dependency gene that functions in replication fork restart and repair." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-3363.
Cheng, Tiewei, Beat Roth, and David J. McConkey. "Abstract 4578: Identification of a gene expression signature that is associated with dependency on FGFR3 rather than EGFR in bladder cancer cells." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4578.
Edenbrandt, C.-M., S. Gershagen, P. Femlund, R. Wydro, J. Stenflo, and Å. Lundwall. "GENE STRUCTURE OF VITAMIN K-DEPENDENT PROTEIN S; A REGION HOMOLOGOUS TO SEX HORMONE BINDING GLOBULIN (SHBG) REPLACES THE SERINE PROTEASE REGION OF FACTORS IX, X AND PROTEIN C." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644640.
It has recently been shown that the similarity between coagulation factors IX, X and protein C in the protein sequence is also evident in the organization of their genes. To further elucidate the relation of protein S to the other vitamin K-dependent clotting factors, we are now characterizing the human protein S gene. The size of the gene was estimated to be more than 45 kb, by hybridization of a cDNA for human protein S with chromosomal DNA in a Southern blot.We have isolated three overlapping clones from a human genomic DNA library in bacteriophage λ Charon 4A, which cover approximately 40 kb of the gene. The clones have been mapped by single- and double restriction enzyme digestion. Genomic subclones in pUC 18 which hybridize with cDNA probes for protein S have been isolated and sequenced to establish the intron/exon structure of the gene. The 5’- part of the human protein S gene closely resembles the corresponding part of the genes for factors IX, X and protein C. However, the thrombin sensitive region (amino acids 46-75), which is unique for protein S among the vitamin K-dependent clotting factors, is coded for by a separate exon. The 3'- end of the protein S gene, coding for amino acids 247-635, is not homologous to the catalytic region of the vitamin K-dependent serine proteases but shows a significant homology to human sex hormone binding globulin (SHBG).
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Eichler, C., J. Fromme, J. Puppe, W. Malter, S. Paepke, and M. Warm. "Abstract P4-08-21: Gene expression profiling – a decision impact analysis – Decision dependency on OncotypeDX and EndoPredict as a function of oncological work experience." In Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-p4-08-21.
Grubbs, Clinton J., Yian Wang, Ming You, Vernon Steele, Daniel Boring, and Ronald Lubet. "Abstract 962: Similar preventive effects of naproxen and NO-naproxen in a chemically-induced model of urinary bladder cancer: Dose dependency, gene expression and toxicity." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-962.
Lifschitz, Eliezer, and Elliot Meyerowitz. The Relations between Cell Division and Cell Type Specification in Floral and Vegetative Meristems of Tomato and Arabidopsis. United States Department of Agriculture, February 1996. http://dx.doi.org/10.32747/1996.7613032.bard.
Meristems were the central issue of our project. Genes that are required for cell division, cell elongation, cell proliferation and cell fate were studied in the tomato system. The analysis of the dUTPase and threonine deaminase genes, along with the dissection of their regulatory regions is completed, while that of the RNR2 and PPO genes is at an advanced stage. All these genes were isolated in our laboratory. In addition, 8 different MADS box genes were studied in transgenic plants and their genetic relevances discovered. We have also shown that a given MADS box gene can modify the polarity of cell division without affecting the fate of the organ. In vivo interaction between two MADS box genes was demonstrated and the functional dependency of the tomato agamous gene on the TM5 gene product established. We have exploited the Knotted1 meristematic gene in conjunction with tomato leaf meristematic genes to show that simple and compound leaves and, for that matter, sepals and compound leaves, are formed by two different developmental programs. In this context we have also isolated and characterized the tomato Knotted1 gene (TKnl) and studied its expression pattern. A new program in which eight different meristematic genes in tomato will be studied emerged as a result of these studies. In essence, we have shown that it is possible to study and manipulate plant developmental systems using reverse genetic techniques and have provided a wealth of new molecular tools to interested colleagues working with tomato. Similarly, genes responsible for cell division, cell proliferation and cell fate were studied in Arabidopsis floral meristems. Among these genes are the TSO1, TSO2, HANABA TARANU and UNUSUAL FLORAL ORGANS genes, each affecting in its own way the number of pattern of cell divisions, and cell fate, in developing Arabodopsis flowers. In addition, new methods have been established for the assessment of the function of regulatory gene action in the different clonal layers of developing floral meristems.
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Savaldi-Goldstein, Sigal, and Todd C. Mockler. Precise Mapping of Growth Hormone Effects by Cell-Specific Gene Activation Response. United States Department of Agriculture, December 2012. http://dx.doi.org/10.32747/2012.7699849.bard.
Plant yield largely depends on a complex interplay and feedback mechanisms of distinct hormonal pathways. Over the past decade great progress has been made in elucidating the global molecular mechanisms by which each hormone is produced and perceived. However, our knowledge of how interactions between hormonal pathways are spatially and temporally regulated remains rudimentary. For example, we have demonstrated that although the BR receptor BRI1 is widely expressed, the perception of BRs in epidermal cells is sufficient to control whole-organ growth. Supported by additional recent works, it is apparent that hormones are acting in selected cells of the plant body to regulate organ growth, and furthermore, that local cell-cell communication is an important mechanism. In this proposal our goals were to identify the global profile of translated genes in response to BR stimulation and depletion in specific tissues in Arabidopsis; determine the spatio-temporal dependency of BR response on auxin transport and signaling and construct an interactive public website that will provide an integrated analysis of the data set. Our technology incorporated cell-specific polysome isolation and sequencing using the Solexa technology. In the first aim, we generated and confirmed the specificity of novel transgenic lines expressing tagged ribosomal protein in various cell types in the Arabidopsis primary root. We next crossed these lines to lines with targeted expression of BRI1 in the bri1 background. All lines were treated with BRs for two time points. The RNA-seq of their corresponding immunopurified polysomal RNA is nearly completed and the bioinformatic analysis of the data set will be completed this year. Followed, we will construct an interactive public website (our third aim). In the second aim we started revealing how spatio-temporalBR activity impinges on auxin transport in the Arabidopsis primary root. We discovered the unexpected role of BRs in controlling the expression of specific auxin efflux carriers, post-transcriptionally (Hacham et al, 2012). We also showed that this regulation depends on the specific expression of BRI1 in the epidermis. This complex and long term effect of BRs on auxin transport led us to focus on high resolution analysis of the BR signaling per se. Taking together, our ongoing collaboration and synergistic expertise (hormone action and plant development (IL) and whole-genome scale data analysis (US)) enabled the establishment of a powerful system that will tell us how distinct cell types respond to local and systemic BR signal. BR research is of special agriculture importance since BR application and BR genetic modification have been shown to significantly increase crop yield and to play an important role in plant thermotolerance. Hence, our integrated dataset is valuable for improving crop traits without unwanted impairment of unrelated pathways, for example, establishing semi-dwarf stature to allow increased yield in high planting density, inducing erect leaves for better light capture and consequent biomass increase and plant resistance to abiotic stresses.
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Gal-On, Amit, Shou-Wei Ding, Victor P. Gaba, and Harry S. Paris. role of RNA-dependent RNA polymerase 1 in plant virus defense. United States Department of Agriculture, January 2012. http://dx.doi.org/10.32747/2012.7597919.bard.
Objectives: Our BARD proposal on the impact of RNA-dependent RNA polymerase 1 (RDR1) in plant defense against viruses was divided into four original objectives. 1. To examine whether a high level of dsRNA expression can stimulate RDR1 transcription independent of salicylic acid (SA) concentration. 2. To determine whether the high or low level of RDR1 transcript accumulation observed in virus resistant and susceptible cultivars is associated with viral resistance and susceptibility. 3. To define the biogenesis and function of RDR1-dependent endogenous siRNAs. 4. To understand why Cucumber mosaic virus (CMV) can overcome RDR1-dependent resistance. The objectives were slightly changed due to the unique finding that cucumber has four different RDR1 genes. Background to the topic: RDR1 is a key plant defense against viruses. RDR1 is induced by virus infection and produces viral and plant dsRNAs which are processed by DICERs to siRNAs. siRNAs guide specific viral and plant RNA cleavage or serve as primers for secondary amplification of viral-dsRNA by RDR. The proposal is based on our preliminary results that a. the association of siRNA and RDR1 accumulation with multiple virus resistance, and b. that virus infection induced the RDR1-dependent production of a new class of endogenous siRNAs. However, the precise mechanisms underlying RDR1 induction and siRNA biogenesis due to virus infection remain to be discovered in plants. Major conclusions, solutions and achievements: We found that in the cucurbit family (cucumber, melon, squash, watermelon) there are 3-4 RDR1 genes not documented in other plant families. This important finding required a change in the emphasis of our objectives. We characterized 4 RDR1s in cucumber and 3 in melon. We demonstrated that in cucumber RDR1b is apparently a new broad spectrum virus resistance gene, independent of SA. In melon RDR1b is truncated, and therefore is assumed to be the reason that melon is highly susceptible to many viruses. RDR1c is dramatically induced due to DNA and RNA virus infection, and inhibition of RDR1c expression led to increased virus accumulation which suggested its important on gene silencing/defense mechanism. We show that induction of antiviral RNAi in Arabidopsis is associated with production of a genetically distinct class of virus-activated siRNAs (vasiRNAs) by RNA dependent RNA polymerase-1 targeting hundreds of host genes for RNA silencing by Argonaute-2. Production of vasiRNAs is induced by viruses from two different super groups of RNA virus families, targeted for inhibition by CMV, and correlated with virus resistance independently of viral siRNAs. We propose that antiviral RNAi activate broad-spectrum antiviral activity via widespread silencing of host genes directed by vasiRNAs, in addition to specific antiviral defense Implications both scientific and agricultural: The RDR1b (resistance) gene can now be used as a transcription marker for broad virus resistance. The discovery of vasiRNAs expands the repertoire of siRNAs and suggests that the siRNA-processing activity of Dicer proteins may play a more important role in the regulation of plant and animal gene expression than is currently known. We assume that precise screening of the vasiRNA host targets will lead in the near future for identification of plant genes associate with virus diseases and perhaps other pathogens.
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Zhong, Yi. NF-1 Dependent Gene Regulation in Drosophila Melanogaster. Fort Belvoir, VA: Defense Technical Information Center, April 2004. http://dx.doi.org/10.21236/ada471891.
Prusky, Dov, and Jeffrey Rollins. Modulation of pathogenicity of postharvest pathogens by environmental pH. United States Department of Agriculture, December 2006. http://dx.doi.org/10.32747/2006.7587237.bard.
Until recently, environmental pH was not considered a factor in determining pathogen compatibility. Our hypothesis was that the environmental pH at the infection site, which is dynamically controlled by activities of both the host and the pathogen, regulates the expression of genes necessary for disease development in Colletotrichum gloeosporioides and Sclerotinia sclerotiorum. This form of regulation ensures that genes are expressed at optimal conditions for their encoded activities.Pectate lyase encoded by pelB, has been demonstrated to play a key role in virulence of C. gloeosporioides in avocado fruit. Polyglacturonase synergism with oxalic acid production is considered to be an essential pathogenicity determinant in the interactions of S. sclerotiorum with its numerous hosts. A common regulatory feature of these virulence and pathogenicity factors is their dependence upon environmental pH conditions within the host niche to create optimal conditions for expression and secretion. In this proposal we have examined, 1) the mechanisms employed by these fungi to establish a suitable pH environment, 2) the molecular levels at which genes and gene products are regulated in response to environmental pH, and 3) the molecular basis and functional importance of pH-responsive gene regulation during pathogenicity. The specific objectives of the proposal were: 1. Characterize the mechanism of local pH modulation and the effect of ambient pH on the expression and secretion of virulence factors. 2. Provide evidence that a conserved molecular pathway for pH-responsive gene expression exists in C. gloeosporioides by cloning a pacC gene homologue. 3. Determine the role of pacC in pathogenicity by gene disruption and activating mutations. Major conclusions 1. We determined the importance of nitrogen source and external pH in the secretion of the virulence factor pectate lyase with respect to the ambient pH transcriptional regulator pacC. It was concluded that nitrogen source availability and ambient pH are two independent signals for the transcriptional regulation of genes required for the disease process of C. gloeosporioides and possibly of other pathogens. 2. We also determined that availability of ammonia regulate independently the alkalinization process and pelB expression, pecate lyase secretion and virulence of C. gloeosporioides. 3. Gene disruption of pacC reduced virulence of C. gloeosporioides however did not reduced fully pelB expression. It was concluded that pelB expression is regulated by several factors including pH, nitrogen and carbon sources. 4. Gene disruption of pacC reduced virulence of S. slcerotiourum Creation of a dominant activating
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Adam, Zach, and Eran Pichersky. Degradation of Abnormal Proteins in Chloroplasts of Higher Plants. United States Department of Agriculture, August 1994. http://dx.doi.org/10.32747/1994.7568768.bard.
In this study we attempted to get a better understanding of processes involved in the degradation of abnormal proteins i chloroplasts. To achieve this goal, we used a number of complementary approaches. We first characterized the expression of the two subunits of Clp protease. We demonstrated that both of them were expressed in chloroplasts in a constitutive fashion, but the expression of the regulatory subunit ClpC was enhanced by light. We generated a mutant the lumenal protein OEE33 which was targeted to the stroma in in vitro experiments. In the wrong compartment it was found unstable, and characterization of its degradation revealed that it was degraded by a soluble, ATP-dependent serine protease, which are also the characteristics of Clp protease. In search of other homologues of bacterial proteases, we found that chloroplasts contain a homologue of the FtsH protease. It is an ATP-dependent metallo-protease, bound to the stromal side of the thylakoid membrane, whose expression is dependent on light. The gene encodig this protease was cloned and characterized. In attempt to generate Arabidopsis mutant plants impaired in their capability to degrade abnormal chloroplast proteins, we fused the gene for mistargeted OEE33 to the streptomycin-detoxifying gene. This chimeric gene was introduced into Arabodipsis plants, to generate transformed plants. This transformants plants were sensitive to streptomycin due to the rapid turn-over of the chimeric protein. Seeds from these plants were then chemically mutagenised, and seedlings were selected for their capability to grow on streptomycin. The ability of these mutant transformants to grow on streptomycin is presumably due to stabilization of the chimeric protein. These plants will allow us in the future to identify the effected genes, which are likely to be involved in the protein degradation process.
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Pichersky, Eran, Alexander Vainstein, and Natalia Dudareva. Scent biosynthesis in petunia flowers under normal and adverse environmental conditions. United States Department of Agriculture, January 2014. http://dx.doi.org/10.32747/2014.7699859.bard.
The ability of flowering plants to prosper throughout evolution, and for many crop plants to set fruit, is strongly dependent on their ability to attract pollinators. To that end many plants synthesize a spectrum of volatile compounds in their flowers. Scent is a highly dynamic trait that is strongly influenced by the environment. However, with high temperature conditions becoming more common, the molecular interplay between this type of stress and scent biosynthesis need to be investigated. Using petunia as a model system, our project had three objectives: (1) Determine the expression patterns of genes encoding biosynthetic scent genes (BSGs) and of several genes previously identified as encoding transcription factors involved in scent regulation under normal and elevated temperature conditions. (2) Examine the function of petunia transcription factors and a heterologous transcription factor, PAPl, in regulating genes of the phenylpropanoid/benzenoid scent pathway. (3) Study the mechanism of transcriptional regulation by several petunia transcription factors and PAPl of scent genes under normal and elevated temperature conditions by examining the interactions between these transcription factors and the promoters of target genes. Our work accomplished the first two goals but was unable to complete the third goal because of lack of time and resources. Our general finding was that when plants grew at higher temperatures (28C day/22C night, vs. 22C/16C), their scent emission decreased in general, with the exception of a few volatiles such as vanillin. To understand why, we looked at gene transcription levels, and saw that generally there was a good correlation between levels of transcriptions of gene specifying enzymes for specific scent compounds and levels of emission of the corresponding scent compounds. Enzyme activity levels, however, showed little difference between plants growing at different temperature regimes. Plants expressing the heterologous gene PAPl showed general increase in scent emission in control temperature conditions but emission decreased at the higher temperature conditions, as seen for control plants. Finally, expression of several transcription factor genes decreased at high temperature, but expression of new transcription factor, EOB-V, increased, implicating it in the decrease of transcription of BSGs. The major conclusion of this work is that high temperature conditions negatively affect scent emission from plants, but that some genetic engineering approaches could ameliorate this problem.
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Xu, Jin-Rong, and Amir Sharon. Comparative studies of fungal pathogeneses in two hemibiotrophs: Magnaporthe grisea and Colletotrichum gloeosporioides. United States Department of Agriculture, May 2008. http://dx.doi.org/10.32747/2008.7695585.bard.
Plant pathogenic fungi have various life styles and different plant infection strategies. Hemibiotrophs like Magnaporthe grisea and Colletotrichum species develop specialized structures during plant infection. The goal of this study was to identify, characterize, and compare genes required for plant infection in M. grisea and C. gloeosporioides. Specific objectives are to: 1) further characterize genes identified in the preliminary studies of C. gloeosporioides and M. grisea;2) identify and characterize additional fungal genes tagged by GFP; and 3) identify in planta growth and appressorium-specific genes by subtractive hybridization and transcript profiling by the LongSAGE method. In this study, the PI and Co-PI collaborated closely on studies in M. grisea and C. gloeosporioides. In M. grisea, REMI and ATMT were used to transform the wildtype with promoter-less EGFP constructs. A total of 28 mutants defective in different plant infection processes or expressing EGFP during plant infection were identified. Genes disrupted in five selected mutants have been identified, including MG03295 that encodes a putative Rho GTPase. In transformant L1320, the transforming vector was inserted in the MIRI gene that encodes a nuclear protein. The expression of MIRI was highly induced during infection. Deletion and site-directed mutagenesis analyses were used to identify the promoter regions and elements that were essential for induced in planta expression of MIRI. This was the first detailed characterization of the promoter of an in planta gene in M. grisea and the MIRI promoter can be used to monitor infectious growth. In addition, the Agilent whole-genome array of M. grisea was used for microarray analyses with RNA samples from appressoria formed by the wild-type shain and the pmkl and mstl2 mutants. Over 200 genes were downregulated in the mst I 2 and pmkl mutants. Some of them are putative transcription factors that may regulate appressorium formation and infectious hyphal growth. In C. gloeosporioides, various REMI mutants showing different pathogenic behavior were identified and characterized. Mutants N3736 had a single insertion and was hyper-virulent. The gene disrupted in mutant3736 (named CgFMOI) encodes a FAD-dependent monooxygenase. Expression analyses linked the expression of the CgFMOI gene with the necrotrophic phase of fungal infection, and also suggest that expression of CgFMOl is unnecessary for the first stages of infection and for biotrophy establishment. All CgFMOl-silenced mutants had reduced virulence. In REMI mutant N159, the tagged gene encodes a putative copper transporter that is homologue of S. cerevisiae CTR2. In yeast, Ctr2 is a vacuolar transporter for moving copper from the vacuole to the cytoplasm. The gene was therefore termed CgCTR2. In addition to characterization of CgCTR2, we also conducted comparative analyses in M. grisea. The M. grisea CgCTR-2 homolog was isolated, knockout strains were generated and characterized and the M. grisea was used to complement the Nl 59 C. gloeosporioides mutant. Overall, we have accomplished most of proposed experiments and are in the process of organizing and publishing other data generated in this project. For objective 3, we used the microarray analysis approach. Several genes identified in this study are novel fungal virulence factors. They have the potential to be used as targets for developing more specific or effective fungicides. In the long run, comparative studies of fungal genes, such as our CgCTR2 work, may lead to better disease control strategies.
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Gottesfeld, Joel M. Inhibition of Estrogen Receptor-Dependent Gene Transcription By a Designed Ligant. Fort Belvoir, VA: Defense Technical Information Center, July 1998. http://dx.doi.org/10.21236/ada357673.
Cnaani, Avner, Gordon Grau, Darren Lerner, and Sheenan Harpaz. Gastrointestinal osmoregulatory activity in Tilapia and its effects on growth, an opportunity for fish diet developments. United States Department of Agriculture, July 2014. http://dx.doi.org/10.32747/2014.7594393.bard.
Fish living in freshwater and seawater environments experience constant osmotic pressure between their internal body and the surrounding water. Regulation of ion and water balance under these conditions is highly energetic demanding, and eventually, affects the fish growth. While the role of the gills in osmoregulation was extensively studied, the osmoregulatory activity of the gastrointestinal tract is less known. In this study we characterized the tilapia intestine as a multifunctional organ, having a role in both nutrition and in ion regulation. We studied the pituitary endocrine regulation of intestinal salinity adaptation, the salinity-dependent physiological activity along different intestinal sections, and specific genes that are linking nutrient absorption with ion and acid-base regulation. The results of this study indicate that different intestinal sections developed various specific activities. Their endocrine regulation is now better understood, a large data-set of salinity dependent gene transcript was developed, as well as new tools and methods to study new aspects of intestinal physiology.
