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Data publikacji: 4 czerwca 2021
Data aktualizacji: 23 lutego 2023

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1

Mariotti, Marco. "Computational genomics of selenoproteins". Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/295583.

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Selenoproteins are a diverse class of proteins containing selenocysteine, the 21st aminoacid. Selenocysteine is inserted co-translationally, recoding very specific UGA codons through a dedicated machinery. Standard gene prediction programs consider UGA only as translational stop, and for this reason selenoprotein genes are typically misannotated. In the past years, we developed computational tools to predict selenoproteins at genomics scale. With these, we characterized the set of selenoproteins across many sequenced genomes, and we inferred their phylogenetic history. We dedicated particular attention to selenophosphate synthetase, a selenoprotein family required for selenocysteine biosynthesis, that can be used as marker of the selenocysteine coding trait. We show that selenoproteins went through a very diverse evolution in different lineages. While very conserved in vertebrates, selenoproteins were lost independently in many other organisms. Using genome sequencing, we traced with precision the path of genomic events that lead to recent selenoprotein extinctions in certain fruit flies.
Les selenoproteïnes s’agrupen en una classe heterogènia de proteïnes les quals contenen selenocysteïna, l’aminoàcid 21. La selenocisteïna és insertada durant el procés de traducció, recodificant codons UGA molt específics, mitjançant una maquinàiria dedicada. Els programes estàndard de predicció de gens interpreten el codó UGA només com a senyal d’stop de la traducció, i per aquesta raó els gens de selenoproteïness solen estar mal anotats. En els darrers anys, hem desenvolupat eines computacionals per a predir selenoproteïnes a escala genòmica. Amb aquestes, hem caracteritzat el conjunt de selenoproteïnes en aquells genomes que han estat seqüenciats, inferint la seva història filogenèitca. Hem dedicat especial ateníció a la família selenophosphate synthetase, selenoproteïna necessària per a la síntesi de selenocisteïna, i que per tant pot ser utilitzada com a marcador de codificació de selenocisteïna Mostrem que les selenoproteïnes han patit una evolució molt diversa en diferents llinatges. Tot i que es troben molt conservades en vertebrats, les selenoproteïnes van ser perdudes de manera independent en molts altres organismes. Gràcies a la sequenciació de genomes, vam traçar amb precisió els esdeveniment que van portar a l’extinció de selenoproteïnes a diverses espècies de drosòfila.
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2

Mariotti, Marco 1984. "Computational genomics of selenoproteins". Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/295583.

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Selenoproteins are a diverse class of proteins containing selenocysteine, the 21st aminoacid. Selenocysteine is inserted co-translationally, recoding very specific UGA codons through a dedicated machinery. Standard gene prediction programs consider UGA only as translational stop, and for this reason selenoprotein genes are typically misannotated. In the past years, we developed computational tools to predict selenoproteins at genomics scale. With these, we characterized the set of selenoproteins across many sequenced genomes, and we inferred their phylogenetic history. We dedicated particular attention to selenophosphate synthetase, a selenoprotein family required for selenocysteine biosynthesis, that can be used as marker of the selenocysteine coding trait. We show that selenoproteins went through a very diverse evolution in different lineages. While very conserved in vertebrates, selenoproteins were lost independently in many other organisms. Using genome sequencing, we traced with precision the path of genomic events that lead to recent selenoprotein extinctions in certain fruit flies.
Les selenoproteïnes s’agrupen en una classe heterogènia de proteïnes les quals contenen selenocysteïna, l’aminoàcid 21. La selenocisteïna és insertada durant el procés de traducció, recodificant codons UGA molt específics, mitjançant una maquinàiria dedicada. Els programes estàndard de predicció de gens interpreten el codó UGA només com a senyal d’stop de la traducció, i per aquesta raó els gens de selenoproteïness solen estar mal anotats. En els darrers anys, hem desenvolupat eines computacionals per a predir selenoproteïnes a escala genòmica. Amb aquestes, hem caracteritzat el conjunt de selenoproteïnes en aquells genomes que han estat seqüenciats, inferint la seva història filogenèitca. Hem dedicat especial ateníció a la família selenophosphate synthetase, selenoproteïna necessària per a la síntesi de selenocisteïna, i que per tant pot ser utilitzada com a marcador de codificació de selenocisteïna Mostrem que les selenoproteïnes han patit una evolució molt diversa en diferents llinatges. Tot i que es troben molt conservades en vertebrats, les selenoproteïnes van ser perdudes de manera independent en molts altres organismes. Gràcies a la sequenciació de genomes, vam traçar amb precisió els esdeveniment que van portar a l’extinció de selenoproteïnes a diverses espècies de drosòfila.
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3

Santesmasses, Ruiz Didac 1978. "Selenoproteins across the tree of life: Methods and applications". Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/565634.

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La selenocïsteina és coneguda com a l'aminoàcid 21. Les selenoproteïnes incorporen selenocïsteina en resposta a codons UGA específics mitjançant un mecanisme de recodificació, el qual és present en els tres dominis de la vida, però no en tots els organismes. Els programes estàndard per a la predicció de gens consideren UGA només com a codó stop, per aquesta raó l'anotació de selenoproteínes és, generalment, incorrecte. Hem desenvolupat mètodes computacionals per a la predicció de selenoproteïnes. Mitjançant l'aplicació d'aquestes i altres eines, hem caracteritzat selenoproteïnes a través de l'Arbre de la Vida, on hem observat una evolució dinàmica en la utilització de selenocïsteina en els diferents llinatges. Hem caracteritzat l'abundància i distribució de selenoproteïnes en el microbioma humà. Hem caracteritzat les selenoproteïnes presents a Lokiarchaeota, les quals presenten trets eucariòtics. Finalment hem dedicat especial atenció als insectes, en els quals una progressiva reducció en el nombre de selenoproteïnes culminà en múltiples extincions de selenoproteïnes en esdeveniments evolutius independents.
Selenocysteine is known as the 21st amino acid. Selenoproteins incorporate selenocysteine in response to specific UGA codons through a recoding mechanism, which present in the three domains of life, but not in all organisms. Standard gene prediction programs consider UGA only as stop, and selenoproteins are normally misannotated. We have developed computational methods for prediction of selenoproteins. By applying these and other tools, we have characterized selenoproteins across the Tree of Life, showing a diverse evolution of the utilization of selenocysteine in different lineages. We have characterized the abundance and distribution of selenoproteins in the human microbiota. We characterized the selenoproteins in Lokiarchaeota, which have some eukaryotic-like features. Finally we gave special attention to insects, in which a progressive reduction in the number of selenoproteins culminated in multiple independent selenoprotein extinctions.
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4

Evangelista, Jaqueline Pesciutti. "Selenoproteínas: Seril-tRNA Sintetase e as selenoproteínas do Trypanosoma brucei". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-13112014-171709/.

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O aminoácido selenocisteína (Sec) representa a principal forma biológica de selênio sendo requerida uma complexa maquinaria molecular para sua síntese e incorporação co-traducional em selenoproteínas. A Seril-tRNA sintetase (SerRS) inicia essa via, aminoacilando o Ser-tRNASec (SelC) com uma serina e também aminoacila os tRNAsSer. Sendo assim, um dos focos deste trabalho foi estudar a interação da SerRS de Trypanosoma brucei (T. brucei) com os tRNAsSer e o SelC utilizando a técnica de anisotropia de fluorescência para determinar suas constantes de dissociação. Em Kinetoplastidae, além da via de síntese de selenocisteína, há três selenoproteínas: SelT, SelK e SelTryp. No entanto, pouco se sabe a respeito das mesmas, sendo o estudo destas selenoproteínas o outro foco deste trabalho. Os fragmentos de DNA que codificam estas selenoproteínas foram subclonados em vetor de expressão pET 28a e 29a para posterior uso em células de Escherichia coli (E. coli). Para as proteínas SelK e SelTryp os ensaios de expressão apresentaram resultados insuficientes para dar continuidade aos experimentos planejados, pois o rendimento foi baixo e a purificação não foi possível. Já com a proteína SelT, devido à grande dificuldade encontrada para tornà-la solúvel, descobriu-se, no decorrer do trabalho, que tratava-se de uma proteína de membrana, ocasionando mudanças de alguns objetivos previamente propostos e consequentemente busca por novas estratégias. Conseguiu-se expressá-la na de forma solúvel e purificá-la por cromatografias. Ensaios realizados no SEC-MALLS mostraram uma estabilidade do complexo proteína-detergente. Com a TbSerRS é possível concluir que a organização de especificidade de ligação da enzima com seus ligantes se dá crescentemente: SelC>tRNASer7>tRNASer3a>tRNASer3b. E com as selenoproteínas do T. brucei faz-se necessários novas contruções para SelK e SelTryp e dar continuidade aos experimentos com a SelT tentando cristalizá-la, já que prototolo para a obtenção do complexo proteína-detergente está montado e estabilizado.
Selenocysteine (Sec) amino acid is the major biological form of selenium and requires a complex molecular machinery for its synthesis and co-translational incorporation into selenoproteins. The Seryl-tRNA synthetase (SerRS) starts this biosynthesis and matches the tRNASec (SELC) with a serine and the tRNAsSer, therefore the focus of this study is on SerRS of Trypanosoma brucei (T. brucei) and tRNAsSer and SELC interactions, with fluorescence anisotropy techinic to determinat dissociation constants. Three selenoproteins, namely SelT, SelK and SelTryp, besides the route of selenocysteine synthesis there be in Kinetoplastidae. DNA fragments that coding for these selenoproteins were subcloned in 28a and 29a to use into Escherichia coli (E. coli) cells. For Selk and SelTryp proteins, the expression protocol did not show an unsatisfactory result to continue the experiments. Many difficulties were encountered in studies with Selt protein, mainly in attempts to make it soluble. Our analyses revealed SelT was a membrane protein, therefore it could cause changes in some objectives and search for new strategies. It could be expressed and purified in cromatographis. SEC-MALLS assays showed a stability of the protein detergent complex. With TbSerRS is possible to conclude that the organization of binding specificity of the enzyme with its ligands occurs increasingly: SelC>tRNASer7>tRNASer3a>tRNASer3b. And selenoproteins in T. brucei, it is necessary for new constructions to SelK and SelTryp to continue the experiments trying to crystallizes SelT, since prototolo for obtaining the protein-detergent complex is assembled and stabilized.
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5

Zhou, Xiaodong. "The effect of estrogen status on selenium metabolism in female rats". Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1179976985.

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6

Mallion, Stephen Nicholas. "The development of the time differential perturbed directional correlation technique for biomedical applications". Thesis, University of Surrey, 1994. http://epubs.surrey.ac.uk/844138/.

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Consideration is given to the use of the time differential perturbed directional correlation (TDPDC) technique in biomedical applications such as structural studies of the selenoproteins. Mathematical models of the perturbed directional correlations show that the application of the TDPDC technique to the study of the electric quadrupole interactions experienced by an ensemble of probe nuclei bound to a protein is capable of yielding the fraction of probe nuclei occupying each of a number of distinct types of binding site in the protein, the strength, symmetry and inhomogeneity of the nuclear quadrupole interaction occurring at each different type of site and, if the environment of the protein is a viscous solution, the diffusion constant for the protein in the solution, from which the associated correlation time and hence the radius of the protein may be derived. A time spectrometer employing a pair of barium fluoride (BaF2) scintillation counters was designed and constructed to allow TDPDC experiments to be performed. The optimum time resolution of the spectrometer was found to be 354+/-10 ps for the 1.173 and 1.332 MeV gamma-rays emitted in the decay of 60Co. The characteristics of the spectrometer were inferior to those of similar systems which are described elsewhere. A number of improvements to the spectrometer that was used in this work have been suggested. The manner in which various deviations from the ideal experimental arrangement affect both the observed perturbed directional correlation and the optimum methods of conducting TDPDC experiments has been carefully considered. Of particular importance was the effect of source decentring, since the employed apparatus does not allow the radioactive source to be precisely centred. It was found that the implications of source decentring are that the values of the parameters describing the perturbation of the directional correlation must be derived from a single TDPDC spectrum, as must those of a number of additional parameters which are of little interest. The viability of this procedure was investigated by carrying out a TDPDC study of the 356-81 keV gamma-gamma cascade in 133Cs, taking account of the interference from sum-coincidence effects and competing cascades. From the TDPDC spectrum that was obtained, the smearing effects of the finite time resolution of the spectrometer were partially removed by deconvolution, resulting in an unfolded time spectrum to which attempts were made to fit a suitable model. Although it was not possible to achieve a satisfactory fit, a number of potential remedies for the poor fit have been proposed. A TDPDC study of the 121-280 keV gamma-gamma cascade in 75As was performed for the purpose of assessing the feasibility of using the TDPDC technique in future investigations employing 75Se-labelled selenoproteins. Account was again taken of the interference from sum-coincidence effects and competing cascades. A bid to deconvolve the smeared TDPDC spectrum that was acquired was not successful, and so attempts were made to fit to the smeared spectrum a model which allowed for the finite time resolution of the spectrometer. The fitting proved to be problematic, indicating that it would be difficult to apply the TDPDC technique to an investigation of 75Se-labelled selenoproteins. However, this conclusion is perhaps unduly pessimistic because some of the problems that arose in the feasibility study will not be present in practice when a 75Se-labelled selenoprotein is used. The available evidence suggests that 73Se offers advantages over 75Se as a radiolabel in TDPDC studies of the selenoproteins.
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7

Terry, Emily Nicole. "Regulation of selected selenoproteins in porcine and bovine skeletal muscle". Online access for everyone, 2008. http://www.dissertations.wsu.edu/Thesis/Spring2008/e_terry_041108.pdf.

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8

Cockman, Eric Michael. "Post-Transcriptional Regulation of Selenoprotein S". Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1562593531805034.

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9

Rosario, Sarah. "Bacterial Selenoproteins: A Role in Pathogenesis and Targets for Antimicrobial Development". Doctoral diss., University of Central Florida, 2009. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/2655.

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Selenoproteins are unique proteins in which selenocysteine is inserted into the polypeptide chain by highly specialized translational machinery. They exist within all three kingdoms of life. The functions of these proteins in biology are still being defined. In particular, the importance of selenoproteins in pathogenic microorganisms has received little attention. We first established that a nosocomial pathogen, Clostridium difficile, utilizes a selenoenzyme dependent pathway for energy metabolism. Following this initial characterization, we demonstrate that this pathway is linked to production of toxins by this organism. Finally, we show that interruption of selenium metabolism is a viable pathway for development of antimicrobials against this, and other selenoprotein dependent pathogens. We investigated whether Stickland reactions (paired amino acid fermentation) might be at the heart of C. difficile's bioenergetic pathways. Growth of C. difficile on Stickland pairs yielded large increases in cell density in a limiting basal medium, demonstrating these reactions are tied to ATP production. Selenium supplementation was required for this increase in cell yield. Analysis of genome sequence data reveals genes encoding the protein components of two key selenoenzyme reductases; glycine and D-proline reductase. These selenoenzymes were expressed upon addition of the corresponding Stickland acceptor (glycine, proline or hydroxyproline). Purification of the selenoenzyme D-proline reductase revealed a mixed complex of PrdA and PrdB (SeCys containing) proteins. D-proline reductase utilized only D-proline but not L-hydroxyproline, even in the presence of an expressed and purified proline racemase. The enzyme was found to be independent of divalent cations, and zinc was a potent inhibitor. These results show that Stickland reactions are key to the growth of C. difficile and that the mechanism of D-proline reductase may differ significantly from similar enzymes from non-pathogenic species. C. difficile pathogenesis is due to the production of toxins, A and B, members of the large clostridial cytotoxin family. Previous studies have shown that toxin production by this organism is influenced by the composition of the growth medium. We examined the impact of Stickland acceptor amino acids (Stickland acceptors; glycine, proline and hydroxyproline) on growth kinetics and yield, protein synthesis, toxin production and gene expression. Although addition of Stickland acceptors moderately increases growth yield and total protein synthesis, there does not appear to be a clear impact on entry into stationary phase. Glycine dramatically increases the amount of toxin released into the growth medium. Conversely, the addition of hydroxyproline suppresses toxin production. We examine possible mechanisms of regulation and demonstrate that CodY, a regulator of toxin gene transcription does not appear to mediate this effect. Given the importance of selenium dependent Stickland reactions to C. difficile growth and toxin production we aimed to examine the efficacy of blocking such pathways as a means of antimicrobial development. Selenide is the only known substrate for selenophosphate synthetase, the first enzyme involved in the specific incorporation of selenium into selenoproteins. We have identified a stable complex formed upon reaction of auranofin (a gold containing drug) with selenide in vitro. Auranofin potently inhibits the growth of C. difficile but does not similarly affect other clostridia that do not utilize selenoproteins to obtain energy. Moreover, auranofin inhibits the incorporation of radioisotope selenium (75Se) in selenoproteins in both E. coli, the prokaryotic model for selenoprotein synthesis, and C. difficile without impacting total protein synthesis. Auranofin blocks the uptake of selenium and results in the accumulation of the auranofin-selenide adduct in the culture medium. Addition of selenium in the form of selenite or L-selenocysteine to the growth media significantly reduces the inhibitory action of auranofin on the growth of C. difficile. Based on these results, we propose that formation of this complex and the subsequent deficiency in available selenium for selenoprotein synthesis is the mechanism by which auranofin inhibits C. difficile growth. The antimicrobial potential of blocking selenium metabolism is further demonstrated in the dental pathogen Treponema denticola. We show that auranofin blocks the growth this organism which also participates in Stickland fermentation. In addition, we provide evidence that the antimicrobial action of stannous salts against T. denticola is also mediated through inhibition of the metabolism of selenium. These studies clearly show that, at least in a subset of microbes that use selenium for the synthesis of selenoproteins, the need for this metalloid can be a useful target for future antimicrobial development.
Ph.D.
Department of Biomolecular Science
Burnett College of Biomedical Sciences
Biomedical Sciences PhD
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10

Waschulewski, Ingo Herbert 1962. "Effect of dietary methionine on selenomethionine metabolism and utilization for selenoproteins". Thesis, The University of Arizona, 1988. http://hdl.handle.net/10150/276933.

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The effects of dietary methionine (Met) on the utilization of selenium (Se) from stored tissue Se and dietary selenomethionine (SeMet) for glutathione peroxidase (GSH-Px) synthesis were studied in male rats. Plasma, liver and muscle Se significantly increased when rats were fed 0.5 mg Se/kg diet as SeMet in a Met-deficient diet for 21 d, whereas tissue GSH-Px activities decreased 43-50% during the SeMet supplementation period, suggesting that Se is deposited as SeMet in general body proteins. By calculation, a significant lower percentage of Se was associated with GSH-Px in Met-deficient as compared to Met-supplemented rats. Dietary Met supplementation increased the incorporation of 75Se from 75SeMet into specific rat selenoproteins in addition to liver GSH-Px. Overall, these results suggest that intact SeMet is preferentially incorporated non-specifically into general body proteins in Met-deficient rats, whereas with supplemental Met, more SeMet is degraded and the released Se used for specific selenoprotein synthesis. (Abstract shortened with permission of author.)
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11

Talbot, Sarah Ryann. "The effects of trivalent arsenicals and thioredoxin reductase inhibitors on selenium metabolism in lung cell culture models". Master's thesis, University of Central Florida, 2007. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/3730.

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Arsenic exposure, through various routes, is associated with the development of cancer of the skin, lung, liver, kidney, and bladder. Treatment of cells in culture with trivalent arsenicals has been shown to increase reactive oxygen species (ROS). In particular, monomethylarsonous acid (MMAIII), a trivalent metabolite of arsenite, is highly cytotoxic and possibly carcinogenic. Three trivalent arsenicals; arsenite, arsenic trioxide (ATO), and MMAIII, are also known inhibitors of the selenoprotein thioredoxin reductase (TrxR). Selenium, an essential micronutrient in mammals, is needed in the form of selenocysteine for activity of this enzyme and other selenoproteins. TrxR is part of a key component of the cell's ability to defend against ROS. It has been speculated that TrxR is also involved directly in selenium metabolism, but this has yet to be demonstrated in vivo. The promoter region of the gene encoding the cytosolic TrxR (TrxR1) also contains an antioxidant responsive element (ARE). The ARE is activated by the transcription factor, Nrf2, which is governed by the Nrf2/Keap1 response, and can be triggered by certain oxidants. ATO and arsenite both inhibited incorporation of selenium into selenoproteins. Auranofin, a gold chemotherapeutic inhibitor of TrxR1, also inhibited selenoprotein synthesis. These results seem to support the hypothesis that TrxR1 is needed for selenoprotein synthesis. However, siRNA mediated reduction of TrxR1 did not block incorporation of selenium into selenoproteins. It is likely that ATO and auranofin are forming As-Se and Au-Se complexes, respectively. We also found that exposure of primary lung fibroblasts (WI-38) to MMAIII led to increased synthesis of TrxR1. This increase was dependent on the activation of transcription of the TrxR1 gene, specifically mediated through the ARE element. These results indicate exposure to MMAIII induces the Nrf2 response. The results obtained in these studies aid in both our understanding of the carcinogenic potential of arsenic as well as give new insight into the mechanism of action of emerging cancer drugs.
M.S.
Department of Molecular Biology and Microbiology
Burnett College of Biomedical Sciences
Molecular and Microbiology MS
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12

Rogers, Sarah Elizabeth. "A selenocysteine containing αHL for single molecule studies". Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572843.

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Proteins containing selenocysteine (selenoproteins) have been found to exist in organisms from all domains of life. Selenoproteins are important for many in vivo processes such as the removal of reactive oxygen containing species (ROS), redox disulfide shuffling reactions, and pro-hormone activation. Structurally and functionally analogous to cysteine, selenocysteine's lower pKa appears to be the defining chemical difference between these two amino acids. Using a single-molecule electrical recording technique, rate constants for the reaction of selenocysteine with small molecule disulfides were obtained over a pH range of 6 - 10. Analogous single molecule ~riments carried out ~ .. - using cysteine, revealed that, after correcting for the ratio of selenolate to selenol and thiolate to thiol based on the pKa of each amino acid, the nuc1eophilicity of selenocysteine was comparable to that of cysteine. The selenium atom of the selenylsulfide bond was found to be substantially more electrophilic than a sui fur atom of the analogous disulfide bond and the leaving group ability of the selenolate of selenocysteine compared to the thiolate of cysteine were found to be comparable. Another biologically relavant interaction that occurs in vivo is the reaction between selenocysteine and organoarsenic (Ill) molecules. It is known that arsenic (Ill) compounds are toxic to organisms, and that this toxicity stems from the ability to coordinate to the thiol and selenol groups of the cysteine and selenocysteine residues within proteins. The reaction of selenocysteine with an organoarsenic species was investigated at the single molecule level over the pH range 6.5 - 8.5. By carrying out an analogous reaction between cysteine and the organoarsenic (Ill) species, it was found that selenocysteine and cysteine exhibit similar reaction rates. The organoarsenic reagent could exist in a range of different protonation states in solution and it was concluded that the rate of reaction was governed by the equilibrium of the arsenic molecule, where only some of the forms were reactive towards the selenocysteine and cysteine groups.
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13

RUSOLO, Fabiola. "From hepatocarcinoma to breast cancer: selenoproteins as link between two different reality". Doctoral thesis, Università degli studi del Molise, 2017. http://hdl.handle.net/11695/76092.

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Il selenio è un minerale essenziale presente di fondamentale importanza per la salute umana. È noto principalmente per la sua attività antiossidante, chemopreventive, per le proprietà anti-infiammatorie e antivirali, (Papp et al. 2007) il cui deficit è stato riconosciuto come un fattore responsabile di condizioni fisiopatologiche, tra cui malattie cardiache, disturbi neuromuscolari, cancro, infertilità maschile e l'infiammazione. Gran parte delle sue azioni benefiche sulla salute umana è attribuita alla sua presenza all'interno di almeno 25 proteine (selenoproteine) (Papp et al. 2007). Sta diventando sempre più evidente come il cancro e i suoi aspetti non dipendono solo dalla genetica delle cellule tumorali ma anche dall’ambiente circostante [tessuto stromale (cellule immunitarie, fibroblasti, miofibroblasti, citochine e tessuto vascolare), nonché dalla matrice extracellulare], necessario per la sopravvivenza, la crescita, la proliferazione delle cellule tumorali e le metastasi. Le cellule infiammatorie e i mediatori sono presenti nel microambiente nella maggior parte, se non in tutti i tumori, indipendentemente dal fattore scatenante lo sviluppo (al. Leonardi et 2012). L’epatocarcinoma (HCC) e il cancro alla mammella (BC) ne sono degli esempi. Il fegato è un organo ormone-sensibile e diverse evidenze suggeriscono che gli ormoni sessuali e i loro recettori svolgono un ruolo nella carcinogenesi del fegato (Wang et al. 2006). Il continuo stress ossidativo, la concomitante alterazione della sintesi degli enzimi antiossidanti nell’epatocarcinoma e nel cancro alla mammella, una compromessa sintesi e secrezione degli ormoni sessuali hanno gettato le basi per ricercare nelle selenoproteine un grande aiuto, non solo nel mitigare questi meccanismi, ma anche nel modulare il signaling ormonale esacerbante l’epatocarcinogenesi. Lo scopo di questo lavoro di tesi è stato quello di identificare le selenoproteine, la cui de-regolazione fosse potenzialmente associata all’epatocarcinogenesi e al cancro alla mammella. Queste indagini preliminari indirizzano gli studi futuri alla comprensione di come le cellule del cancro alla mammella possano influenzare l’epatocarcinogenesi mediante la secrezione di ormoni, citochine, chemochine e fattori di crescita e come le cellule dell’epatocarcinoma possano esercitare un controllo sulla progressione del cancro alla mammella. Inoltre, sarà interessante esaminare come la modulazione dell'espressione delle selenoproteine, mediante trattamento con il solo selenio o in combinazione con le molecole chemioterapiche, possa influenzare il signaling chiave di questi due cancri.
Selenium is an essential trace mineral of fundamental importance to human health. It is known primarily for its antioxidant activity, for its chemopreventive, anti-inflammatory and antiviral properties, (Papp et al. 2007) hence its deficiency has been recognized as a contributing factor to pathophysiological conditions, including heart disease, neuromuscular disorders, cancer, male infertility and inflammation. Much of its beneficial influence on human health is attributed to its presence within at least 25 proteins (Selenoproteins) (Papp et al. 2007). It is becoming more evident how the cancer and its the behaviour not dependent only on the genetics of tumor cells but also by surrounding milieu [stromal tissue (immune cells, fibro¬blasts, myofibroblasts, cytokines, and vascular tissue), as well as the surrounding extracellular matrix], necessary for tumor cells survival, growth, proliferation and metastasis. Inflammatory cells and mediators are present in the microenvironment of most, if not all, tumors, irrespective of the trigger for development (Leonardi et al. 2012). Hepatocarcinoma (HCC) and Breast Cancer (BC) are examples. The liver is a hormone-sensitive organ and a several lines of evidence suggest that sex hormones and their receptors play a role in liver carcinogenesis (Wang et al. 2006). Continuous oxidative stress, impaired synthesis of antioxidant enzymes in HCC and in BC, un-regulated synthesis and secretion of sex hormones laid the foundation for research into selenoproteins a great help, not only to mitigate these mechanisms, but also to modulate the hormonal signaling exacerbating the hepatocarcinogenesis. The aim of thesis has been to identify selenoproteins, whose de-regulation was, potentially, associated to hepatocarcinogenesis and to breast cancer. These preliminary investigations direct future studies to understand how BC cells can influence the hepatocarcinogenesis through the secretion of hormones, cytokines, chemokines and growth factors and how the HCC cells can exercise control on breast cancer progression. Furthermore, it will be interesting to investigate how the modulation of selenoproteins, by treatment with selenium alone or in combination with chemotherapeutic molecules, might influence the key signaling of these two cancers.
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14

Löwinger, Maria. "Sulforaphan und Selen : Einfluss auf Phase II Enzyme und Selenoproteine sowie deren Effekt auf die entzündungsvermittelte Dickdarmkanzerogenese". Phd thesis, Universität Potsdam, 2010. http://opus.kobv.de/ubp/volltexte/2011/5186/.

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Das ITC SFN und der Mikronährstoff Se sind bekannt als chemopräventive Inhaltsstoffe von Gemüse der Brassica-Familie, welcher auch Brokkoli angehört. Die Wirkungen von sowohl SFN als auch Se beruhen auf zahlreichen verschiedenen Mechanismen. Es existieren jedoch Schnittstellen, an welchen Interaktionen beider Substanzen möglich sind. Basierend auf diesem Wissen wurden in dieser Arbeit Wechselwirkungen zwischen SFN und Se auf die Aktivität sowie Expression von Phase II Enzymen und Selenoproteinen untersucht. Der Einfluss der Kombination von SFN und Se auf die unter physiologischen Bedingungen stattfindende Proliferation und Apoptose war ebenso Gegenstand der Arbeit wie die Modulation von Entzündungsprozessen sowie der Tumorentstehung während der entzündungsverstärkten Colonkanzerogenese im Mausmodell. Das hinsichtlich seiner Wirksamkeit mit aus GRA hydrolysiertem SFN zunächst als vergleichbar befundene synthetische SFN wurde für die Untersuchung im AOM/DSS-induzierten Colontumormodell gewählt und in Kombination mit 3 verschiedenen Selendiäten verabreicht. Der Einfluss von SFN und Se auf Phase II Enzyme und Selenoproteine entlang des GIT war organabhängig und nach 4 Wochen geringer als nach 7 Tagen. Die schwächere Induktion deutet auf eine Anpassung des Organismus hin. Ein SFN-vermittelter Effekt auf NQO1 war im Selenmangel am deutlichsten. Die Aktivität des Selenoproteins TrxR wurde hingegen erst bei ausreichender Selenversorgung durch SFN beeinflusst. Die als Nrf2-Zielgen bekannte und in der Hierarchie der Selenoproteine einen hohen Rang einnehmende GPx2 konnte in bestimmten Organen bereits unter selenarmen Bedingungen durch SFN induziert werden. Eine Überexpression des Enzyms war jedoch nicht möglich. SFN steigerte, unabhängig vom Selenstatus, im oberen Abschnitt des GIT und im Colon die Aktivität der GST. Eine Induktion des eigenen Metabolismus wäre somit denkbar. Im Falle eines Mangels an GPx2 wurde GPx1 bei hinreichender Selenversorgung stärker exprimiert, allerdings konnte sie die Funktion von GPx2 nicht völlig erset-zen. Im Selenmangel kann die Aktivitätssteigerung der TrxR im Dünndarm, dem Ab-schnitt der Selenabsorption, als ein Versuch der GPx2-Kompensation angesehen werden. SFN war nicht in der Lage, über eine Aktivierung des Nrf2/ARE-Signalweges kompensatorische Effekte zu induzieren. Apoptotische Prozesse wurden unter physiologischen Bedingungen nur marginal durch SFN und Se moduliert. Das elektrophile ITC konnte lediglich im Selenmangel Apoptose im luminalen Bereich der Colonkrypten induzieren. Die durch supranutritive Selenkonzentration induzierte Apoptose im Kryptengrund wurde nicht durch SFN beeinflusst. Einer bei Abwesenheit der GPx2 erhöhten Apoptoserate im Kryptengrund wirkte SFN bei adäquater Selenversorgung entgegen, war indessen proapoptotisch unter selendefizienten Konditionen. Der Einfluss von SFN auf die Entzündung war deutlich abhängig vom Selenstatus. Während SFN im Selenmangel anscheinend prooxidative Prozesse induzierte und die Entzündungssymptome verschlimmerte, wirkte es unter adäquatem Selenstatus an-tiinflammatorisch. Den vergleichsweise milden Grad der Entzündung im selensupplementierten Status konnte SFN nicht zusätzlich beeinflussen. SFN veränderte die Inzi-denz colorektaler Tumore nicht. Ein, die Tumorinitiation blockierender SFN-Effekt durch direkte Hemmung der metabolischen Aktivierung des Prokanzerogens im selenadäquaten Zustand scheint offensichtlich. Eine Überversorgung mit Se kann protektiv im Hinblick auf Entzündung oder Colonkanzerogenese sein, jedoch bewirkt SFN keinen zusätzlichen Schutz. Kombinationseffekte von SFN und Se in Bezug auf Phase II Enzyme, Selenoproteine und Apoptose sowie die entzündungsverstärkte Colonkanzerogenese sind nicht eindeutiger Natur und können, abhängig vom Endpunkt, synergistische oder antagonistische Züge aufweisen. Eine bei Selendefizienz deutlichere Wirkung von SFN kann mit Hilfe der gesteigerten Aktivierung von Nrf2 erklärt werden, dies muss jedoch nicht von Vorteil sein. Bei adäquater Selenversorgung kann SFN kurzfristig antiinflammatorische und antikanzerogene Prozesse induzieren. Von einer längerfristigen ständigen SFN-Aufnahme in Form von GRA-reichen Brassicacea ist jedoch abzuraten, da von einer Adaptation auszugehen ist. Die Wirkung von SFN innerhalb der komplexen Pflanzenmatrix bleibt Gegenstand zukünftiger Untersuchungen.
Sulforaphane (SFN), a versatile actor derived from broccoli or other brassicaceae, is proposed to be a dietary anticarcinogen. Together with an adequate selenium status, it has been associated with a decreased risk for developing certain forms of cancer. In our mouse model, we investigate the influence of SFN and Se on the expression and activity of selenoproteins and phase II enzymes as well as the effects on inflammation triggered colon carcinogenesis. SFN increased NQO1 activity and protein expression significantly in the ileum, in both, Se-deficiently and Se-adequately fed animals. TrxR activity was increased in Se-adequately compared to Se-deficiently fed mice, SFN positively affected TrxR activity only in the former ones. An increase of GPx2 protein expression by SFN was observed in the ileum of mice of both diets. GPx1 reacts sensitively on Se supply. GST was the only enzyme analyzed being significantly increased by SFN on activity level in the colon. All AOM/DSS treated animals showed an inflammation, which was attenuated by SFN within Se-adequacy. In contrast, Se-deficient animals showed a more severe inflammation. The administration of SFN therefore seemed to enhance this even more and to be not beneficial in this case. SFN inhibited colon carcinogenesis in Se-adequate mice when being administered together with AOM. To summarize, both, GPx2 and TrxR, require selenium in order to be synthesized. In contrast to TrxR, the SFN-mediated induction of GPx2, the highest ranking selenoprotein, does not depend on additional selenium supply. Whereas distinct effects by SFN were observed in the ileum, only GST was influenced by SFN in the colon. SFN seems to induce its own metabolism. In conclusion, SFN and Se attenuate inflammation and colon carcinogenesis, preferably by means of up-regulating the endogenous defense system and inhibiting the metabolic activation of AOM.
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15

Alonis, Melenie Lee. "Selenotrisulfide Derivative of Alpha-Lipoic acid: Evaluation in a Cell Culture Model for Potential Use as a Topical Antioxidant". Master's thesis, University of Central Florida, 2005. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/3451.

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Selenium is a required micronutrient in mammalian cells. It is incorporated in the form of selenocysteine into selenoenzymes such as glutathione peroxidase and thioredoxin reductase, and is absolutely required for activity. Thioredoxin reductase is necessary for reduction of oxidized thioredoxin and therefore plays a major role in maintaining the redox status of the cell. Glutathione peroxidase is responsible for reducing peroxides into their corresponding alcohols and water. Together, these selenoenzymes constitute a significant part of the cell's arsenal to defend itself against oxidative stress. Exogenous sources of oxidative stress, such as UV radiation, are capable of generating reactive oxygen species (ROS). Elevated levels of ROS can lead to covalent modifications of lipids, nucleic acids, and proteins within a cell. This damage has been implicated in the development of cancer and degenerative diseases. As the skin is the first level of defense for UV radiation, skin cancer is an obvious concern. Previous studies have demonstrated a protective effect against UV-induced cytotoxicity when selenium compounds were administered to skin cells in cell culture models. Topical selenium application to mice has also been shown to reduce UV damage to skin. Although a variety of chemical forms of selenium are available in nutritional supplements, the efficiency by which they are used for selenoprotein synthesis varies greatly. It is debated within the selenium research community which form is best for use as a supplement. In this study, we have focused on a selenotrisulfide derivative of alpha-lipoic acid (LASe). We have examined its utilization for selenoprotein synthesis through radiolabeling studies (75Se) in a human keratinocyte cell line (HaCaT). We have determined that is incorporated into selenoproteins with nearly the same efficiency as selenite and L-selenocysteine. We have also determined that LASe is far more efficient as a supplement in cell culture than selenate or L-selenomethionine, two forms of selenium commonly used as supplements. LASe was also found to protect HaCaT keratinocytes from UV- induced cytotoxicity. Cells pretreated with LASe and exposed to 500J/m2 and 750J/m2 of broadband (UVA/UVB) UV radiation showed greater survival than untreated controls in a dose –dependent manner. Cells pre-treated either with lipoic acid or selenium in the form of selenite alone also observed protection. Nonetheless, these finding are significant given that LASe was previously shown to penetrate the skin better than other forms of selenium. These results indicate that LASe has the potential for use as a topical antioxidant upon further testing in animal studies.
M.S.
Department of Molecular Biology and Microbiology
Burnett College of Biomedical Sciences
Molecular Biology and Microbiology
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16

Riese, Cornelia. "Einfluss des Geschlechts auf den Selenmetabolismus und die Biosynthese von Selenoproteinen". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2007. http://dx.doi.org/10.18452/15653.

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Se ist ein essentielles Spurenelement, das seine biologische Aktivität als Selenocystein in den katalytischen Untereinheiten von Selenoproteinen entfaltet. Es wird als Supplement in der Prävention und Therapie einiger Volkskrankheiten wie Autoimmunerkrankungen und Krebs eingesetzt. Die verfügbaren Ergebnisse der klinischen Studien deuten auf geschlechtsspezifische Unterschiede in der Wirksamkeit von Se. Aus diesem Grunde sollte in der vorliegenden Arbeit die Biosynthese von Selenoproteinen in männlichen und weiblichen Mäusen als Modellorganismus für höhere Säugetiere analysiert und verglichen werden. Die gewonnenen Ergebnisse belegen eindeutig, dass die mRNA Konzentrationen von Selenoprotein P, der 5''-Iodothyronin-Deiodase Typ 1 und der extrazellulären Glutathion-Peroxidase 3 geschlechtsspezifische Unterschiede aufweisen. Dieser Dimorphismus ist jedoch nicht konstant, sondern variiert von Gewebe zu Gewebe und zeigt überdies auch eine Abhängigkeit vom Se-Status der Tiere und dem untersuchten Mausstamm. Überraschenderweise korrelieren die resultierenden Proteinmengen nicht linear mit den Unterschieden der mRNA Konzentrationen. Besonders die 5''-Iodothyronin-Deiodase Typ 1 zeigt ausgeprägte Unterschiede in Leber und Niere, wobei sich die Geschlechtsdimorphismen auf mRNA- und Protein-Ebene unterschiedlich stark ausprägen und vom Se-Status beeinflusst werden. Zusammengenommen zeigt diese Arbeit, dass die Expression von Selenoproteinen auf zwei Kontrollebenen geschlechtsspezifisch reguliert wird: über steroidabhängige Gentranskription werden unterschiedliche mRNA Konzentrationen abhängig vom Mausstamm, Alter und Se-Status in den Geweben exprimiert, und über noch nicht eindeutig identifizierte Mechanismen wird die Effektivität, mit der diese Transkripte in die entsprechenden Selenoproteine übersetzt werden, geschlechtsspezifisch kontrolliert. Diese Se-abhängige Regulation der Biosyntheserate, die vermutlich über eine veränderte Translationseffizienz erfolgt, stellt ein sehr überraschendes Ergebnis dar. Sollte es sich in menschlichen Proben bestätigen, so könnten diese Ergebnisse helfen, die geschlechtsspezifischen Befunde in den klinischen Supplementationsstudien zu verstehen und entsprechend abgestimmte Empfehlungen für eine unterschiedliche Supplementation von Mann und Frau zu erarbeiten.
Selenium is an essential trace element and acts as Selenocystein in the catalytic entity of selenoproteins. It is currently in use as supplement in the prevention and therapy of a variety of diseases including autoimmune diseases and cancer. The epidemiological and clinical data indicate that the effectiveness of Se supplementations is sex-specific. Therefore, this thesis was initiated to analyse and compare the expression of selenoproteins in male and female mice as a suitable model organism for higher mammals. The experimental data clearly indicate that selenoprotein P, type I 5'' iodothyronine deiodinase and the secreted glutathione peroxidase 3 display sex-specific differences in mRNA concentrations. The sexual dimorphic expression patterns of these selenoproteins are not constant but depend on the tissue, the Se-status of the animals and the specific mouse strain analysed. Surprisingly, no direct correlation is observed when mRNA levels and expressed protein concentrations are compared. This becomes very obvious in the case of type I 5'' iodothyronine deiodinase in liver and kidney. Both mRNA and protein levels differ between the sexes in a discordant and Se-dependent manner. Taken together, this thesis indicates that selenoprotein expression is regulated in a sex-specific manner by two different mechanisms. First of all, steroid-dependent gene transcription gives rise to sexually dimorphic mRNA levels in the different tissues. Mouse strain, age and Se-status influence this process. Secondly, the sexes differ profoundly with respect to the efficiency of selenoprotein biosynthesis from a given number of transcripts. Presumably, this process involves Se-dependent translational control mechanisms that have not been described before. Under the assumption that these results can be verified with human samples, it is conceivable that this new mechanism might help to explain some of the enigmatic sex-specific effects observed in human supplementary studies and that sex-specific supplementation regimen need to be worked out in the long run.
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17

Olsson, Maja. "Tenomodulin, serum amyloid A and the serum amyloid A receptor selenoprotein S : implications for metabolic disease /". Göteborg : Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 2010. http://hdl.handle.net/2077/21942.

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18

Mistry, Hiten. "Selenium, selenoproteins and factors which might interact with them relating to oxidative stress, in normal and pre-eclamptic pregnancies". Thesis, University of Nottingham, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491024.

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Pre-eclampsia (PE) is a pregnancy specific condition that affects 2-3% of women. At present the cause of PE is unknown, however the main pathological features are impaired placentation, with inadequate invasion of the spiral arteries by syncytiotrophoblasts, and systemic endothelial damage, contributing to increased perinatal and maternal morbidity and mortality. PE may have life time consequences for the fetus in terms of greater predisposition to adult cardiovascular disease.
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19

Aichler, Michaela. "Influence of selenium on pancreatic carcinogenesis and the role of the selenoproteins cytosolic and mitochondrial thioredoxin reductase in the pancreas". [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:100-opus-3076.

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20

Zhao, Wenchao [Verfasser]. "Ribosome profiling of selenoproteins in vivo reveals consequences of pathogenic Secisbp2 missense mutations : The establishment of translating ribosome affinity purification / Wenchao Zhao". Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1222588757/34.

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21

Dalla, Puppa Lisa. "Investigation of the effects of selenium and selenoproteins on the activation of microglia and on the protection of brain cells in oxidative stress". [S.l.] : [s.n.], 2006. http://www.diss.fu-berlin.de/2006/402/index.html.

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22

Papp, Laura V., i n/a. "Multiple Levels of Regulation of Human SECIS Binding Protein 2, SBP2". Griffith University. School of Biomolecular and Biomedical Science, 2006. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20070208.145623.

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Selenium is an essential trace mineral of fundamental importance to human health. Its beneficial functions are largely attributed to its presence within a group of proteins named selenoproteins in the form of the amino acid selenocysteine (Sec). Recently, it was revealed that the human selenoproteome consists of 25 selenoproteins, and for many of them their function remains unknown. The most prominent known roles of selenoproteins are to maintain the intracellular redox homeostasis, redox regulation of intracellular signalling and thyroid hormone metabolism. Sec incorporation into selenoproteins employs a unique mechanism that involves decoding of the UGA stop codon. The process requires interplay between distinct, intrinsic features such as the Sec Insertion Sequence (SECIS) element, the tRNASec and multiple protein factors. The work presented in this thesis has focused on characterising the regulation of human SECIS binding protein 2, SBP2, a factor central to this process. Experimental approaches combined with bioinformatics analysis revealed that SBP2 is subjected to alternative splicing. A total of nine alternatively spliced transcripts appear to be expressed in cells, potentially encoding five different protein isoforms. The alternative splicing events are restricted to the 5?-region, which is proposed to be dispensable for Sec incorporation. One of the variants identified, contains a mitochondrial targeting sequence that was capable of targetting SBP2 into the mitochondrial compartment. This isoform also appears to be expressed endogenously within the mitochondria in cells. Previous reports have depicted SBP2 as a ribosomal protein, despite the presence of a putative Nuclear Localisation Signal (NLS). In this study it was found that SBP2 subcellular localisation is not restricted to ribosomes. Intrinsic functional NLS and Nuclear Export Signals (NESs), enable SBP2 to shuttle between the nucleus and the cytoplasm via the CRM1 pathway. In addition, the subcellular localisation of SBP2 appears to play an important role in regulating Sec incorporation into selenoproteins. The subcellular localisation of SBP2 is altered by conditions imposing oxidative stress. Several oxidising agents induce the nuclear accumulation of SBP2, which occurs via oxidation of cysteine residues within a novel redox-sensitive cysteine rich domain (CRD). Cysteine residues were to form disulfide bonds and glutathione-mixed disulfides during oxidising conditions, which are efficiently reversed in vitro by the thioredoxin and glutaredoxin systems, respectively. These modifications negatively regulate selenoprotein synthesis. Cells depleted of SBP2 are more sensitive to oxidative stress than control cells, which correlated with a substantial decrease in selenoprotein synthesis after treatment with oxidising agents. These results provide direct evidence that SBP2 is required for Sec incorporation in vivo and suggest that nuclear sequestration of SBP2 under such conditions may represent a mechanism to regulate the expression of selenoproteins. Collectively, these results suggest that SBP2 is regulated at multiple levels: by alternative splicing, changes in subcellar localisation and redox control.
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23

Papp, Laura V. "Multiple Levels of Regulation of Human SECIS Binding Protein 2, SBP2". Thesis, Griffith University, 2006. http://hdl.handle.net/10072/367554.

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Selenium is an essential trace mineral of fundamental importance to human health. Its beneficial functions are largely attributed to its presence within a group of proteins named selenoproteins in the form of the amino acid selenocysteine (Sec). Recently, it was revealed that the human selenoproteome consists of 25 selenoproteins, and for many of them their function remains unknown. The most prominent known roles of selenoproteins are to maintain the intracellular redox homeostasis, redox regulation of intracellular signalling and thyroid hormone metabolism. Sec incorporation into selenoproteins employs a unique mechanism that involves decoding of the UGA stop codon. The process requires interplay between distinct, intrinsic features such as the Sec Insertion Sequence (SECIS) element, the tRNASec and multiple protein factors. The work presented in this thesis has focused on characterising the regulation of human SECIS binding protein 2, SBP2, a factor central to this process. Experimental approaches combined with bioinformatics analysis revealed that SBP2 is subjected to alternative splicing. A total of nine alternatively spliced transcripts appear to be expressed in cells, potentially encoding five different protein isoforms. The alternative splicing events are restricted to the 5?-region, which is proposed to be dispensable for Sec incorporation. One of the variants identified, contains a mitochondrial targeting sequence that was capable of targetting SBP2 into the mitochondrial compartment. This isoform also appears to be expressed endogenously within the mitochondria in cells. Previous reports have depicted SBP2 as a ribosomal protein, despite the presence of a putative Nuclear Localisation Signal (NLS). In this study it was found that SBP2 subcellular localisation is not restricted to ribosomes. Intrinsic functional NLS and Nuclear Export Signals (NESs), enable SBP2 to shuttle between the nucleus and the cytoplasm via the CRM1 pathway. In addition, the subcellular localisation of SBP2 appears to play an important role in regulating Sec incorporation into selenoproteins. The subcellular localisation of SBP2 is altered by conditions imposing oxidative stress. Several oxidising agents induce the nuclear accumulation of SBP2, which occurs via oxidation of cysteine residues within a novel redox-sensitive cysteine rich domain (CRD). Cysteine residues were to form disulfide bonds and glutathione-mixed disulfides during oxidising conditions, which are efficiently reversed in vitro by the thioredoxin and glutaredoxin systems, respectively. These modifications negatively regulate selenoprotein synthesis. Cells depleted of SBP2 are more sensitive to oxidative stress than control cells, which correlated with a substantial decrease in selenoprotein synthesis after treatment with oxidising agents. These results provide direct evidence that SBP2 is required for Sec incorporation in vivo and suggest that nuclear sequestration of SBP2 under such conditions may represent a mechanism to regulate the expression of selenoproteins. Collectively, these results suggest that SBP2 is regulated at multiple levels: by alternative splicing, changes in subcellar localisation and redox control.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
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24

Dacleu, Siewe Vanessa. "Molecular and structural bases of selenoprotein N dysfunction in diverse forms of congenital muscular dystrophies". Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ127.

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Les Selenoprotéines sont des protéines contenant un résidu sélénocystéine (U) dans leur séquence en acide amines. Vingt-cinq sélénoprotéines constituent le sélénoprotéome humain. Parmi elles, la sélénoprotéine N ou SelenoN ; des mutations dans le gène SELENON donnent lieu à un groupe de dystrophies musculaires congénitales appelées myopathies liées à SELENON. SelenoN est une protéine membranaire glycosylée de 72 kDa localisée dans le réticulum endoplasmique. Sa séquence en acide aminés contient le motif redox SCUG, similaire à celui des thioredoxines réductases. Elle contient de même un domaine EF-hand qui est un domaine de liaison au calcium. Des études ont récemment démontré l’implication de cette protéine dans l’établissement et la maintenance du muscle squelettique. D’autres études ont montré qu’elle joue un rôle dans la protection contre le stress oxydatif et l’homéostasie du calcium. Cependant, le mécanisme catalytique de SelenoN reste inconnu à ce jour. Le projet décrit dans cette thèse s’intéresse à la caractérisation, la cristallisation et la comparaison des SelenoNs d’une bactérie, Candidatus poribacteriae, et du poisson zèbre. Les études bio-informatiques ont démontré que SelenoN bactérienne et du poisson zèbre partagent 37% d’identité et un domaine commun correspondant à un repliement de type thioredoxine de fonction inconnue, contenant le motif redox. Les caractérisations biophysiques ont démontré que les deux protéines sont naturellement bien repliées et riche en hélices α. La protéine bactérienne comportant en C-terminal de sa séquence en acide aminé un domaine thioredoxine additionnel, présente une forme étendue et est sous forme monomérique tandis que la protéine du poisson zèbre est un dimère compact. Des caractérisations biochimiques ont montré que le Ca2+ influence l’oligomérisation ou la conformation de SelenoN du poisson zèbre. Des cristaux initiaux de la protéine eucaryote sous sa forme déglycosylée ont pu être obtenus. La cristallisation de la protéine bactérienne a permis d’obtenir des cristaux appartenant à deux groupes d’espaces, avec des paramètres de cellule différents. Néanmoins, un modèle partiel à 2.3 Å couvrant le domaine C-terminal thioredoxine additionnel de SelenoN bactérienne a été obtenu. L’ensemble de ces résultats permettent de poser les bases de l’étude structure-fonction de SelenoN. L’expression, la purification et la cristallisation ont été optimisées et une stratégie pour résoudre la structure 3D de la protéine est proposée
Selenoproteins are proteins containing a selenocysteine residue (U) in their amino acid sequence. Twenty-five proteins constitute the human selenoproteome. Among them is Selenoprotein N or SelenoN; mutations in the SELENON gene can lead to a group of congenital dystrophies now designated as SELENON-related myopathies. SelenoN is a 72 kDa membrane and glycosylated protein of the endoplasmic reticulum. It handles in its amino acid sequence a redox motif SCUG like the one of thioredoxin reductases, and an EF-hand domain which is a calcium binding site. Recent studies showed the implication of SelenoN in muscle development and maintenance, and position its function at the crossroad between oxidative stress control and calcium homeostasis. However, its catalytic function remains elusive. The research project presented in this thesis concerns the crystallization, characterization and comparison of one bacterial and the zebrafish SelenoNs. Bioinformatics analyses revealed that the two proteins share 37% degree of identity and a common domain which corresponds to a thioredoxin fold of unknown function which includes the redox motif SCUG. From the biophysical characterization, both recombinant proteins are found to be naturally well-folded and enriched in α-helical domains. The bacterial SelenoN which handles an additional C-terminal thioredoxin domain is an extended monomer whereas zebrafish SelenoN is a compact dimer. Biochemical characterization indicated that Ca2+ binding mediates zSelenoN oligomerization. Initial crystals of the zSelenoN in its deglycosylated form were obtained. Bacterial SelenoN crystallization yielded crystals belonging to two different space groups with different cell parameters. An initial partial model covering the C-terminal thioredoxin domain of the bacterial SelenoN was obtained at 2.3Å. Together, these results lay a foundation for the structure-function studies of SelenoN. Conditions for recombinant bacterial and zebrafish SelenoNs expression, purification and crystallization were optimized and strategies for solving the structure are being proposed
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25

Carlisle, Anne E. "Exploring the Role of Selenocysteine Biosynthesis Enzyme SEPHS2 in Cancer". eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1112.

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Selenium is a micronutrient that is used by the selenocysteine biosynthesis pathway to produce the amino acid selenocysteine, which is required in selenoproteins. Many of the 25 human selenoproteins, such as glutathione peroxidases and thioredoxin reductases, play important roles in maintaining cellular redox homeostasis. In this study we characterize how this metabolic pathway is upregulated in cancer cells and how this increase in activity creates a unique vulnerability. We have outlined the evidence and underlying mechanisms for how many metabolites normally produced in cells are highly toxic, and we describe this concept as illustrated in selenocysteine metabolism. My thesis explores how SEPHS2, an enzyme in the selenocysteine biosynthesis pathway, is essential for survival of cancer, but not normal cells. SEPHS2 is required in cancer cells to detoxify selenide, an intermediate that is formed during selenocysteine biosynthesis. Breast and other cancer cells are selenophilic, owing to a secondary function of the cystine/glutamate antiporter SLC7A11 that promotes selenium uptake and selenocysteine biosynthesis, which, by allowing production of selenoproteins such as GPX4, protects cells against ferroptosis. However, this activity also becomes a liability for cancer cells because selenide is poisonous and must be processed by SEPHS2. These results show that SEPHS2 is a cancer specific target and indicates the therapeutic potential of SEPHS2 inhibition in the treatment of cancer. Collectively, this thesis identifies SEPHS2 as a targetable vulnerability of cancer cells, defines the role of selenium metabolism in cancer, and outlines a roadmap for future studies regarding toxic metabolites and cancer.
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26

Dudhal, Swati. "Selenoprotein N as a novel regulator of the muscle progenitor’s cell fate decision process : balancing differentiation and self-renewal". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC288.

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Les mutations du gène codant la sélénoprotéine N (SEPN1) provoquent une myopathie congénitale nommée SEPN1-related myopathy (SEPN1-RM), caractérisée par une faiblesse et une amyotrophie majeures des muscles du cou et du tronc, une scoliose et une insuffisance respiratoire potentiellement létale. SEPN1-RM a été associée avec un stress oxydant, une diminution de la population de cellules souches musculaires (cellules satellites) et des défauts de la régénération musculaire. Avec l’objectif de rechercher les mécanismes impliqués dans ces défauts, et en particulier un rôle potentiel de SEPN1 dans la régulation de l’équilibre entre le renouvellement et la différentiation du pool de cellules satellites, j’ai étudié des cellules satellites primaires de souris knocked-out pour Sepn1et la lignée musculaire murine C2C12 knocked-down pour Sepn1à différents stades de différentiation (cellules quiescentes, myoblastes etmyotubes). Utilisant un système de suspension pour générer une quiescence synchronisée des C2C12, j’ai trouvé que l’absence de SEPN1 dans les cellules en G0 n’est pas incompatible avec la sortie et le retour dans le cycle cellulaire, mais entraîne une moindre sous-régulation de l’expression de deux facteurs clé de la différentiation myogénique (augmentation des transcrits de MYOD1etMYOG par rapport aux contrôles) et une augmentation des niveaux de Cycline D1 (mRNAdeCCND1) en conditions de quiescence. Des études de microarrayet deqRT-PCR ont montré que la déplétion de SEPN1 dans des C2C12 prolifératives est associée à une augmentation significative de l’expression des facteurs de transcription myogéniques MYOG and MYOD1. En parallèle, des études d’immunoblot ont confirmé un niveau augmenté des protéines régulatrices du cycle cellulaire p21 and Cyclin D3 en conditions de prolifération. De plus, des cellules satellites primaires isolées à partir des muscles gastrocnemiusetplantarisde souris KO Sepn1ont montré une fusion accélérée des myoblastes au cours de la différentiation myogénique initiale. Par la suite, j’ai explore les voies mécanistiques impliquées dans ce phénotype cellulaire par western blot et/ou qRT-PCR utilisant des cellulesC2C12 knocked-down pour Sepn1. J’ai pu montrer l’absence de changements nets des voies de l’AMPK et p38, ainsi que du taux d’expression des marqueurs de stress du réticulum endoplasmique GRP78 oucalnexine. Par contre, nos données suggèrent que les voies HDAC5 etmTOR pourraient être impliquées dans le phénotype de différentiation musculaire accélérée. En conclusion, la déplétion de SEPN1 entraîne une quiescence incomplète et une différentiation myogénique accélérée. Par conséquent, ce travail identifie SEPN1 comme un nouveau régulateur du processus de décision du destin cellulaire des progéniteurs musculaires, l’absence de SEPN1 favorisant la différentiation au détriment du renouvellement cellulaire. Ces résultats peuvent contribuer à expliquer la déplétion de la population de cellules satellites et les défauts de régénération observés dans les modèles de SEPN1-RM, et aider à identifier de nouveaux biomarqueurs cellulaires qui seront utiles à l’avenir pour évaluer des approches thérapeutiques
Mutations of Selenoprotein N (SEPN1) cause a congenital myopathy, SEPN1-related myopathy (SEPN1-RM), characterized by severe weakness and wasting of neck and trunk muscles, scoliosis and lethal respiratory failure. SEPN1-RM has been associated with oxidative stress, reduced satellite cell population and defective muscle regeneration. To investigate the underlying mechanisms, particularly a potential role of SEPN1 in regulating the balance between self-renewal and differentiation of the satellite cell pool, I used Sepn1 KO mice primary satellite cells and C2C12 cells knocked down for Sepn1, at different stages of differentiation (quiescent cells, myoblasts and myotubes). Using a suspension system to generate synchronized quiescence on C2C12, I found that Sepn1 absence in G0 cells does not prevent cell cycle exiting and re-entering but prevents normal downregulation of two key myogenic factors (MYOD1 and MYOG mRNAs) and leads to higher Cyclin D1 levels (CCND1 mRNA) in quiescence conditions. Microarray and qRT-PCR studies showed that Sepn1 depletion in proliferative C2C12 cells leads to significant increase in the levels of the transcription factors MYOG and MYOD1. In parallel, immunoblot analysis showed an increased expression of the cell cycle regulator proteins p21 and Cyclin D3. Moreover, primary murine satellite cells isolated from gastrocnemius and plantaris muscles from the Sepn1 KO mice showed increased myoblast fusion during early myogenic differentiation. Next, I explored the mechanistic pathways leading to this cell phenotype by western blots and/or qRT-PCR using Sepn1 knockdown C2C12 cells. I found no clear-cut abnormalities of the AMPK or the p38 mediated pathways, and no consistent changes in the expression of the ER stress markers GRP78 or calnexin. In contrast, our data suggest that HDAC5 and mTOR could be involved in the accelerated differentiation phenotype. Other mechanistic studies are in the progress. In conclusion, lack of SEPN1 leads to incomplete quiescence and accelerated myogenic differentiation. Thus, we identify SEPN1 as a novel regulator of the muscle progenitor’s cell fate decision process and SEPN1 depletion favors differentiation over self-renewal. These results potentially explain the depletion of the satellite cell population and the regeneration defect in SEPN1-RM models, and identify novel biomarkers useful to assess potential therapeutic interventions
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27

Ferreira, Diana Quit?ria Cabral. "Avalia??o do estado nutricional relativo ao sel?nio e da express?o g?nica de selenoprote?nas em pacientes com aterosclerose tratados com estatinas". Universidade Federal do Rio Grande do Norte, 2010. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13489.

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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
The aim of this study was to determine the effects of the use of rosuvastatin in patients with atherosclerosis, in relation to blood parameters of selenium and selenoproteins, and also observe possible changes in gene expression of selenoproteins in these patients. The sample consisted of 27 adult and elderly patients with a clinical diagnosis of coronary artery disease undergoing angioplasty, treated at Natal Hospital Center hospital, Natal, RN. Patients were treated with rosuvastatin 10 mg/day during four months. Anthropometric variables such as body mass index (BMI) and Waist circumference (WC) were measured before and after treatment, as well as lipid profile, blood glucose and liver enzymes (AST and ALT). The diet of the patients was also analyzed using 24-hour diet recall. We analyzed the concentrations of selenium in plasma and erythrocytes, and also the activity of Glutathione Peroxidase and gene expression by Real Time PCR of selenoproteins GPx1, SelP1 and SelN1. Patients had mean age of 61.0 ? 9.4 years, 59.3% were men and 40.7% were women. After four months of treatment there was significant reduction of CA and, according to BMI, most were overweight. The intake of macronutrients, cholesterol, polyunsaturated fatty acids, monounsaturated and saturated was adequate, but the energy and fiber intake was below the recommendations. Regarding the selenium intake was observed a high prevalence of inadequacy. As expected, after treatment with rosuvastatin, a significant reduction in total cholesterol, LDL and glucose, which was not observed for HDL. Selenium concentrations in plasma and erythrocytes showed no changes, keeping within the established cutoffs. We observed a significant increase in GPx enzyme activity and mRNA expression of GPX1 and SEPN1, but not for gene SEPP1. Thus, it was found that treatment with rosuvastatin did not reduce the expression of selenoproteins. More studies are needed to clarify the effects of rosuvastatin on gene expression of selenoproteins in patients with atherosclerosis
Este trabalho tem como objetivo verificar os efeitos do uso da rosuvastatina em pacientes com aterosclerose, em rela??o aos par?metros sangu?neos de sel?nio e selenoprote?nas, bem como observar poss?veis altera??es na express?o g?nica de selenoprote?nas nesses pacientes. A amostra foi constitu?da de 27 pacientes adultos e idosos com o diagn?stico cl?nico de doen?a arterial coronariana submetidos ? angioplastia, atendidos no Natal Hospital Center, Natal, RN. Os pacientes foram tratados com 10mg/dia de rosuvastatina durante 4 meses. Vari?veis antropom?tricas, como ?ndice de Massa Corporal (IMC) e Circunfer?ncia Abdominal (CA), foram medidas antes e ap?s o tratamento, bem como o perfil lip?dico, glicemia e enzimas hep?ticas (AST e ALT). A dieta dos pacientes tamb?m foi analisada utilizando o Recordat?rio alimentar de 24 horas. Foram analisadas as concentra??es do sel?nio no plasma e nos eritr?citos, e tamb?m a atividade da enzima Glutationa Peroxidase e a express?o g?nica por PCR em Tempo Real das selenoprote?nas GPx1, SelP1 e SelN1. Os pacientes apresentaram idade m?dia de 61,0?9,4 anos, sendo 59,3% homens e 40,7% mulheres. Ap?s os quatro meses de tratamento observou-se redu??o significativa da CA e, de acordo com o IMC, a maior parte estava com sobrepeso. A ingest?o dos macronutrientes, colesterol, ?cidos graxos polinsaturados, monoinsaturados e saturados foi adequada, por?m a de energia e fibras estava abaixo das recomenda??es. Com rela??o a ingest?o de sel?nio foi observada uma alta preval?ncia de inadequa??o. Como esperado, ap?s o tratamento com a rosuvastatina, houve redu??o significativa do colesterol total e LDL, bem como da glicemia, o que n?o foi observado para o HDL. As concentra??es de sel?nio no plasma e eritr?citos n?o apresentaram altera??es, se mantendo dentro dos pontos de corte estabelecidos. Foi observado um aumento significante na atividade enzim?tica da GPx e na express?o de mRNA do GPX1 e SEPN1, mas n?o para o gene SEPP1. Dessa forma, foi verificado que o tratamento com a rosuvastatina n?o diminuiu a express?o das selenoprote?nas. Mais estudos s?o necess?rios para esclarecer os efeitos da rosuvastatina sobre a express?o g?nica de selenoprote?nas em pacientes com aterosclerose
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28

Rother, Michael. "Selenoprotein-Biosynthese in Archaea". Diss., lmu, 2002. http://nbn-resolving.de/urn:nbn:de:bvb:19-680.

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29

Roman, Marco <1983&gt. "Development and applications of new analytical methodologies based on HPLC-ICP-MS for trace speciation analysis of selenium in biological samples". Doctoral thesis, Università Ca' Foscari Venezia, 2011. http://hdl.handle.net/10579/1099.

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New methods for the determination of seleno-proteins in human plasma/serum were developed by coupling miniaturized affinity HPLC systems to ORS-ICP-MS and ICP-SFMS detectors. A methods interlaboratory comparison allowed to provide for the first time the indicative reference concentration of individual seleno-proteins in the commercially available BCR-637 human serum. Two methods for seleno-proteins speciation in plasma/serum where applied to investigate their distribution in patients affected by type II diabetes and colorectal cancer, compared to healthy individuals. A new method was then developed for the speciation analysis of Se in rat colon tissues, based on two-dimensional HPLC coupled to ICP-QMS. Five species of Se were isolated, among which glutathione peroxidases 1 and 2, and thioredoxin reductase 1 were potentially identified by MALDI-TOF-MS. The method was transferred to human samples obtaining promising preliminary results.
Sono stati sviluppati nuovi metodi per la determinazione delle seleno-proteine in plasma/siero umani mediante accoppiamento di sistemi miniaturizzati di HPLC di affinità e detector ORS-ICP-MS e ICP-SFMS. Un confronto interlaboratorio tra metodi ha consentito di stimare per la prima volta la concentrazione di riferimento di seleno-proteine nel siero umano commerciale BCR-637. Due metodi per la speciazione di seleno-proteine in plasma/siero sono stati applicati per investigare la loro distribuzione in pazienti affetto da diabete di tipo II e cancro colonrettale, in confronto a soggetti sani. Un nuovo metodo è stato poi sviluppato per la speciazione delle seleno-proteine in tessuti di colon di ratto, basati su HPLC bidimensionale accoppiata con ICP-QMS. Cinque specie del selenio sono state isolate, tra cui glutatione perossidasi 1 e 2, e tioredoxina reduttasi 1 sono state potenzialmente identificate mediante MALDI-TOF-MS. I metodo è stato trasferito a campioni umani ottenendo promettenti risultati preliminari.
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30

Costa, Fernanda Cristina. "Validação da via de biossíntese de selenocisteína e selenoproteínas em Trypanosoma por RNA de interferência". Universidade Federal de São Carlos, 2012. https://repositorio.ufscar.br/handle/ufscar/5398.

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Universidade Federal de Minas Gerais
Selenium (Se) is an essential element found in selenoproteins as the 21st amino acid (Selenocysteine Sec).For the Sec incorporation and the related biosynthetic pathaway, several elements are required: tRNASec, a UGA codon and a Sec insertion sequence (SECIS), a conserved motif downstream of the selenoprotein encoding gene. Selenoproteins generally participate in the cellular redox balance, playing an important role on cell growth and proliferation. These proteins, as well as the the Sec synthesis pathway, are present in members of the Bacteria, Archaea and Eukarya domains, being identified in several protozoa, including the kinetoplastids. Auranofin, a gold-contaning antirheumatic drug, is a known selenoproteins inhibitorand Trypanosoma brucei and Leishmania majorcells are sensitive to this compound, with a LD50 in nanomolar range. This indicates a possible dependence of these parasites on selenoproteins. Theselenophosphate synthetase (SELD/SPS2) is responsible for the formation of monoselenophosphate from selenide and ATP, being essencial for selenoprotein biosynthesis. SPS2 knockdown led to apoptosis under sub-optimal growth conditions. The selenoproteome of these flagellated protozoa consists of distant homologs of the mammalian SelK and SelT, and a novel selenoprotein designated SelTryp, a kinetoplastidspecific protein. The functions of any of these selenoproteins are not known.We have investigated the effect of their downregulation in T. brucei to interpret their possible physiological role. The TbSelK depletion shows no effect on growth under optimal conditions, but the cells became more sensitive to endoplasmic reticulum stress agents and oxidative stress, suggesting that SelK is an ER stress-regulated protein and plays an important role in protecting T. brucei cells from ER stress agent. The TbSelT gene silence by RNA interference hampers the parasite survival, but the sensitivity to the agents tested was not asevident as it was forTbSelK, suggesting a role for TbSelT in protection against stress, but not specifically ER stress. Our results show the importance of selenocysteine and selenoproteins to parasite survival.
Selênio (Se) é um elemento essencial encontrado em selenoproteínas na forma do 21º aminoácido selenocisteína (Sec U). A incorporação co-traducional de Sec depende de uma complexa via de síntese, de um códon de terminação UGA em fase de leitura e uma estrutura terciária do RNA mensageiro conhecida como elemento SECIS. A maioria das selenoproteínas conhecidas participa de processos de manutenção do estado redox das células, tendo um importante papel no crescimento e proliferação celular. Essas proteínas, bem como os componentes da via de síntese de Sec, estão presentes em membros dos domínios de Bactérias, Arquéais e Eucaria, tendo sido identificada em diversos protozoários, incluindo os kinetoplastidas. Auranofin, um composto de ouro usado como agente antireumático, tem sido descrito como um inibidor de selenoproteínas através de sua ligação com o aminoácido selenocisteína e células de Trypanosoma brucei e Leishmania major são altamente sensíveis a este composto, apresentando um LD50 na faixa de nanomolar. Esta evidência indica uma possível dependência destes parasitas por selenoproteínas e consequentemente pela sua via de síntese. A selenofosfato sinetase (SELD/SPS2) é a enzima responsável pela síntese de monoselenofosfato a partir de seleneto e ATP, sendo, portanto uma proteína fundamental na síntese de selenocisteína. Sua depleção levou a apoptose celular quando mantidas em condições de estresse. Esse efeito pode ser causado pela consequente falta das selenoproteínas ou pelo acúmulo de espécies tóxicas de selênio, como o seleneto. Os protozoários apresentam número reduzido de selenoproteínas e kinetoplastidas apresentam 3, duas homólogas distantes de mamíferos, SelK e SelT, e uma nova proteína exclusiva denominada SelTryp, que não apresentam homologia com nenhuma outra proteína descrita. O papel dessas proteínas não é conhecido, e nós investigamos suas possíveis funções através da inibição de sua expressão. A depleção de TbSelK não mostrou efeito sob condições normais, mas tornou as células mais sensíveis a agentes indutores de estresse de retículo endoplasmático, o que nos permite inferir uma função de manutenção da homeostase dessa organela. A depleção de TbSelT causou uma diminuição no crescimento celular, mas o aumento da sensibilidade aos agentes indutores de estresse não foi tão pronunciada como em TbSelK. Nossos resultados revelam a importância de selenocisteína para parasitas, uma vez que esses organismos enfrentam diversos tipos de estresses para manter a viabilidade e a progressão da doença nos diferentes hábitats encontrados ao longo do seu ciclo de vida.
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31

Tobe, Ryuta. "Enzymological studies on selenoprotein biosynthesis". Kyoto University, 2009. http://hdl.handle.net/2433/126536.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(農学)
甲第14875号
農博第1787号
新制||農||975(附属図書館)
学位論文||H21||N4490(農学部図書室)
27297
UT51-2009-K671
京都大学大学院農学研究科応用生命科学専攻
(主査)准教授 栗原 達夫, 教授 渡邊 隆司, 教授 阪井 康能
学位規則第4条第1項該当
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32

Eussner, Ursula. "Selenoprotein P in der kolorektalen Karzinogenese". [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=967777690.

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33

Crosley, L. K. "Molecular mechanisms of selenoprotein gene expression". Thesis, University of Newcastle Upon Tyne, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399315.

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34

Villette, Stephane. "Molecular study of selenoprotein in gene expression". Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391327.

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35

Miller, Susan Mary. "Selenoprotein function and expression in human endothelium". Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/23124.

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In this thesis the selenoproteins expressed by endothelial cells (isolated from various vascular beds and different species) and the modification of their expression through changes in Se supply and activation of second messenger pathways were studied. The ability of sodium selenite and selenomethionine supplementation to prevent oxidative damage in cultured endothelial cells was also examined, as well as the effect of sodium selenite in stabilising nitric oxide. The present study has confirmed the expression of cytoplasmic glutathione peroxidase (cyGPX) and phospholipid hydroperoxide glutathione peroxidase (PHGPX) in human umbilical vein endothelial cells (HUVEC), however thioredoxin reductase (TR) was found to be the predominant selenoprotein expressed accounting for approximately 43% of the total intracellular 75Se-labelled proteins. No extracellular selenoproteins were synthesised by HUVEC. The overall pattern of selenoprotein expression in endothelial cells isolated from different species and from various human tissue showed considerable variation, though differences were less pronounced when comparing the endothelial cells isolated from various human vascular beds and the human endothelial cell line EAhy926. The expression of TR, cyGPX and PHGPX and other unidentified selenoproteins in HUVEC was significantly modified in response to the phorbol ester phorbol-12-myristate 13-acetate (PMA). A 48 hr incubation with PMA led to significantly decreased expression of both TR and PHGPX (approximately half of that found in untreated cells). Whilst the expression of cyGPX was increased approximately two-fold by PMA treatment, a brief exposure to PMA (one minute) produced similar effects on the expression of these selenoproteins, after a 48 hr lag-period. These effects of PMA could be attenuated by the protein kinase C inhibitor, GF109203X. The calcium ionophore A23187 also modified selenoprotein expression, however time cells began to detach. These observations suggest that the A23187 effect may result from toxicity rather than activation of the calcium signalling pathway.
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36

Pagmantidis, Vasileios. "Selenoprotein gene expression and susceptibility to colon cancer". Thesis, University of Newcastle Upon Tyne, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413956.

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37

Takeuchi, Akiko. "RNA-protein interaction in the selenoprotein synthesis machinery". Strasbourg, 2009. http://www.theses.fr/2009STRA6054.

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La sélénocystéine est incorporée co-traductionnellement dans les sélénoprotéines en réponse à un codon UGA habituellement l’un des 3 codons stop. La protéine SBP2 joue un rôle majeur dans ce mécanisme de recodage en se liant à une structure en tige-boucle (SECIS) située dans la région 3’UTR de l’ARNm des sélénoprotéines. Nous avons isolé et caractérisé fonctionnellement SBP2 de Drosophila melanogaster. Par comparison avec SBP2 humaine, nous avons identifié un domaine de liaison à l’ARN additionnel essentiel à la liaison au SECIS et à la sous-unité ribosomique 60S et permettant une sélectivité structurale du SECIS. Des prédictions structurales et des analyses biophysiques ont établi que SBP2 était une protéine globalement désordonnée ou “Intrinsically Disordered Protein” qui ne se replie qu’en présence de partenaires. Enfin, nous avons établi que l’assemblage des mRNP de sélénoprotéines faisait appel à des facteurs communs et présentait de multiples similarités avec celui des sn/snoRNP
The 21st amino acid selenocysteine is encoded by a UGA codon that usually signifies translational termination. Selenoprotein synthesis therefore requires specialized factors. Among these is SBP2 that binds the SECIS, a stem-loop structure in the 3’UTR of selenoprotein mRNAs. In structural analyses of SBP2, we isolated and functionally characterized Drosophila melanogaster SBP2. By comparing it with human SBP2, we identified an additional RNA binding domain that is essential for SECIS and 60S ribosomal subunit binding, and also enables SECIS structure selectivity. In addition, computational and biophysical analyses established that SBP2 is globally unfolded, supporting our hypothesis that SBP2 is an Intrinsically Disordered Protein and becomes folded in the presence of partners yet to be identified. Finally, we searched for potential partners of SBP2 and our results showed that the molecular assembly of selenoprotein mRNPs has many similarities with that of sn/snoRNPs
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38

Bermano, Giovanna. "The regulation of selenoprotein gene expression by selenium". Thesis, University of Aberdeen, 1996. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU089918.

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This thesis focuses on the influence of selenium supply on the expression of selenoproteins and possible mechanisms involved. It examines the effects of selenium on the expression of cytosolic glutathione peroxidase (cGSH-Px), phospholipid hydroperoxide glutathione peroxidase (PHGSH-Px) and type I iodothyronine 5'deiodinase (IDI) in liver, thyroid and heart of the rat. Nutritional studies in animals fed diets with different selenium content have shown that there is differential regulation of the three mRNAs and subsequent protein synthesis within and between organs, suggesting both that mechanisms exist to channel selenium for synthesis of a particular selenoprotein and that there is tissue-specific regulation of selenoprotein mRNAs. Since selenium supply could regulate selenoprotein expression by either transcriptional or post-transcriptional mechanisms, the effects of selenium depletion on the transcription rate of the three genes and their mRNA stability were investigated. Nuclear run-off assays with isolated liver nuclei showed selenium deficiency to have no effect on transcription of the three genes whereas actinomycin D chase experiments, in hepatoma cells, showed that selenium deficiency had no effect on the stability of PHGSH-Px mRNA but decreased the stability of cGSH-Px mRNA. Additionally, studies with hepatoma cells transfected with chimeric constructs of IDI coding region linked to different 3'UTRs showed that cGSH-Px 3'UTR is less efficient than PHGSH-PX 3'UTR in permitting Se-cysteine incorporation when selenium is limiting. In conclusion, the mechanisms of selenoprotein regulation in selenium deficiency involve post-transcriptional controls: in liver, selenium deficiency affects translation of cGSH-Px and PHGSH-Px mRNAs at different extents and differences in the 3'UTR of these two mRNAs could partially explain the differential effect of selenium deficiency on cGSH-Px and PHGSH-Px activities and mRNA abundance, stability and translation.
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39

Takeuchi, Akiko Krol Alain Allmang-Cura Christine. "RNA-protein interaction in the selenoprotein synthesis machinery". Strasbourg : Université de Strasbourg, 2009. http://eprints-scd-ulp.u-strasbg.fr:8080/1133/01/TAKEUCHI_Akiko_2009.pdf.

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Thèse de doctorat : Sciences du Vivant. Aspects moléculaire et cellulaire de la Biologie : Strasbourg : 2009.
Thèse soutenue sur un ensemble de travaux. Titre provenant de l'écran-titre. Bibliogr. 11 p.
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40

Sonet, Jordane. "Synthèse et régulation des sélénoproteines mammifères". Thesis, Pau, 2017. http://www.theses.fr/2017PAUU3050.

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Le Sélénium (Se) est un oligo-élément essentiel qui est incorporé dans une famille indispensable de protéines, les sélénoprotéines, sous la forme d’un résidu acide aminé rare, la sélénocystéine. Dans les études épidémiologiques, il apparait clairement que des faibles niveaux de sélénium dans les fluides biologiques sont associés avec (i) une augmentation du risque de cancers (colon, prostate, poumon) et de maladies cardiovasculaires, (ii) une altération de la fonction immunitaire et (iii) finalement une réduction de l’espérance de vie. Dans le génome humain, vingt-cinq gènes de sélénoprotéine ont été identifiés. Ces gènes expriment, de par la complexité de la régulation du génome, de nombreuses isoformes de chacun des 25 gènes pour constituer le sélénoprotéome. Quand la fonction est connue, ces protéines participent à des processus essentiels de défense antioxydante, d’homéostasie redox et de signalisation redox. Ces enzymes sont finement régulées par l’apport en sélénium et d’autres stimuli cellulaires. Pour comprendre la fonction et la régulation du sélénoprotéome humain, qui est exprimé à un niveau trace, il s’avère critique de développer une stratégie innovante basée sur une approche multidisciplinaire de détection et quantification du sélénium par différents outils de spectrométrie de masse élémentaire (ICP MS) et moléculaire (ESI-MS/MS). Tout d’abord, le sélénium possède un profil isotopique bien particulier avec six isotopes stables (74Se, 76Se, 77Se, 78Se, 80Se and 82Se) qui sert de signature dans nos analyses en ICP-MS ou en ESI-MS/MS. En parallèle, l’utilisation de sélénium isotopiquement enrichi permet également des marquages cellulaires en multiplexing. Ainsi, en couplant des méthodes de séparation en phase liquide (HPLC) ou en gel d’électrophorèse (IEF ou SDS-PAGE échantilloné par ablation laser) avec l’ICP MS, nous avons mis au point plusieurs méthodes permettant la détection de plusieurs sélénoprotéines de manière simultanée dans différentes lignées cellulaires. De plus, un médicament sélénié sous forme de triglycéride obtenu via un mélange d’huile de tournesol et de sélénite a été testé comme source de sélénium non toxique pouvant stimuler la production de sélénoprotéines. Plusieurs lignées cellulaires humaines cancéreuses et non-cancéreuses ont été expérimentées avec succès permettant de valider cette nouvelle source de sélénium dans la synthèse des sélénoprotéines
Selenium (Se) is an essential trace element, which is incorporated as a rare aminoacid, selenocysteine, in twenty five selenoproteins, to constitute the selenoproteome. Selenoprotein family is one of the most important bioactive form of selenium in human health. Initially demonstrated in Kashin Beck and Keshan diseases, selenium deficiency is associated with several pathological conditions, including cancer, neurodegenerative diseases, immune and muscular disorders. Chronic selenium deficiency is hypothesized to decrease antioxidant defenses and redox regulatory pathways through a dysregulation of selenoprotein expression. We are interested in understanding the synthesis and regulation of human selenoproteins, which is critically dependent on the availability of adequate analytical methodology. To understand the function and regulation of human selenoproteome, which is expressed at a trace levels, it appears critical to develop innovative strategies based on a multidisciplinary approach to detect and quantify selenium by various elemental and molecular mass spectrometer tools. First, selenium has a particular isotopic profile with six stable isotope (74Se, 76Se, 77Se, 78Se, 80Se and 82Se) used as a signature in our analysis with ICP-MS or ESI-MS/MS. In parallel, the use of isotopically enriched selenium also allows cellular labelling and tracing of selenoproteins and other seleno-coupounds. By coupling liquid phase separation methods (HPLC) with specific mass spectrometry analytical tools, we have developed several methods for detecting several selenoproteins simultaneously in various human cell lines
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41

Schumacher, Fredrick Ray. "Relation between the selenoprotein gene, selenium and prostate cancer". Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1132766716.

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Thesis (Ph. D.)--Case Western Reserve University, 2006.
[School of Medicine] Department of Epidemiology and Biostatistics. Includes bibliographical references. Available online via OhioLINK's ETD Center.
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42

Schumacher, Fredrick R. "Relation Between the Selenoprotein Gene, Selenium, and Prostate Cancer". Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1132766716.

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43

Wiehe, Lennart [Verfasser]. "Spurenelemente und Selenoproteine bei Neugeborenen mit konnataler Infektion / Lennart Wiehe". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1139254251/34.

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44

Scharpf, Marcus [Verfasser]. "Untersuchungen zur Expression und Verteilung von Selenoprotein P / Marcus Scharpf". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1026789303/34.

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45

Schomburg, Lutz [Verfasser]. "Molekulare Regulation der Selenoprotein-Biosynthese und des Selentransports / Lutz Schomburg". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2009. http://d-nb.info/1023622181/34.

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46

Michaelis, Marten. "Einfluss von Selenoprotein P auf die intestinale Tumorigenese im Mausmodell". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15874.

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Das essentielle Spurenelement Selen (Se) wird als einziges Spurenelement über den genetischen Code als Bestandteil der 21. proteinogene Aminosäure Selenocystein (SeCys) in eine kleine Gruppe von Proteinen eingebaut. Als Bestandteil des aktiven Zentrums dieser Selenoproteine ist Se bzw. SeCys essentiell für deren Funktion. Die Biosynthese der Selenoproteine ist durch eine Reihe von Besonderheiten gekennzeichnet, so z.B. durch eine hierarchisch abgestimmte Versorgung der unterschiedlichen Organe mit dem limitierenden Spurenelement bzw. durch eine hierarchische Versorgung der einzelnen Selenoproteine während ihrer Biosynthese. Für die biologische Verwertung und Verteilung ist das Selenoprotein SePP von zentraler Bedeutung. Transkriptomanalysen haben aufgezeigt, dass gerade in Tumoren die Expression von SePP stark erniedrigt ist. In dieser Arbeit wurde untersucht, inwieweit der Verlust von SePP einen kausalen Einfluss auf die Tumorigenese nimmt. Hierzu wurden zwei transgene Mausmodelle verkreuzt: zum einen Mäuse mit einem partiellen bzw. kompletten genetischen Verlust der SePP-Expression und zum anderen Mäuse mit einer Mutation im APC-Tumorsuppressorgen, welche multiple intestinale Neoplasien (Min) auslöst und als Paradigma in der experimentellen Darmkrebsforschung dient. Der komplette Verlust des SePP-Gens bewirkte eine stark erhöhte Tumorrate im Dünndarm der APCmin-Mäuse. Hierdurch konnte SePP als neuer wichtiger Modulator der APC-abhängigen Tumorigenese etabliert werden. Interessanterweise genügte bereits der Verlust eines einzelnen SePP-Allels, um mehr, größere und weniger differenzierte Adenome im Dünndarm entstehen zu lassen. Diese Beobachtung deutet auf einen entscheidenden Gen-Dosis-Effekt von SePP für die intestinale Tumorigenese hin und könnte damit als weiteres sinnvolles Kriterium zur Feindiagnostik von Darmkrebs dienen. Die molekularbiologischen Untersuchungen der Tumore lassen eine Aktivierung von Zellzyklus-, Angiogenese- und Akutphaseprozessen vermuten. Hierdurch und über die erhöhte Produktion von Wachstumsfaktoren kann die vermehrte Tumorigenese bei SePP-Mangel erklärt werden. Weitergehend konnte auch der Darm, ungeachtet seiner primären Rolle bei der Selenaufnahme, als abhängig von einer regulären SePP-Expression erkannt werden. Somit stellt sich SePP als zentraler Vermittler des Selenmetabolismus dar, und könnte auf lange Sicht als funktioneller Biomarker des Selenstatus für die individuelle Risikoabschätzung etabliert werden.
Selenium (Se) is the only trace element which is encoded in the genome as the 21st proteinogenic amino acid selenocystein (Sec). Se is essential for the catalytic activity of the small group of Sec-containing selenoproteins. The biosynthesis of this group of extraordinary proteins is characterized by several specialities, e.g. the distribution of Se differs between the organs giving rise to a hierarchical biosynthesis of the selenoproteins and there is an intracellular hierarchy of selenoprotein biosynthesis in times of Se depletion. One particular selenoprotein is of central importance for the organification and trafficking of Se within the organism, i.e., Selenoprotein P (SePP). From transcriptome analyses it was deduced that this Se transport protein is markedly reduced in tumours of several origins. The aim of this thesis was to elucidate whether SePP has a causal impact on the tumourigenesis within the intestinal tract. For this purpose, the SePP-KO mouse model with a genetically impaired SePP expression was crossed with the well-established APCmin intestinal tumour model. A stop mutation in the APC tumour suppressor gene causes multiple intestinal neoplasias (Min) in these mice. The combined deletion of SePP caused a sharp increase in tumour incidence in the small intestines of APCmin mice. Interestingly, even the inactivation of only one SePP allele was sufficient to induce more and less well differentiated adenomas in the small intestine. These results indicate that SePP acts as an important modulator of APC dependent tumorigenesis in a gene dose dependent manner. In the long run, SePP might turn out as another valuable biomarker to estimate the individual cancer risk. From a mechanistic point of view, the transcriptome analyses indicate that an impaired SePP expression favors cell cycle progression, angiogenesis and acute phase response. In addition, an elevated production of growth factors in response to SePP deficiency might contribute to the phenotype of bigger and more undifferentiated tumours. Additional analyses of the intestines revealed that the intestinal tract is dependent on a regular SePP expression in order to synthesise its regular set of selenoproteins even so it represents the prime organ of Se absorption. Therefore, SePP represents a central Se transport and storage protein also within the intestinal tract, highlighting its essential role to preserve health and regular Se metabolism.
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47

Tews, Martha [Verfasser]. "Cholesterol als negativer post-transkriptioneller Regulator der Selenoprotein-Expression / Martha Tews". Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1194189547/34.

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48

Hollenbach, Birgit [Verfasser]. "Bedeutung und Regulation von Selenoprotein P in inflammatorischen Erkrankungen / Birgit Hollenbach". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2010. http://d-nb.info/1024865541/34.

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49

Martitz, Janine. "Factors impacting the hepatic selenoprotein expression in matters of critical illness". Doctoral thesis, Humboldt-Universität zu Berlin, 2017. http://dx.doi.org/10.18452/18033.

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Selenoproteine spielen eine wichtige Rolle in der antioxidativen Abwehr und bei Immunreaktionen. Der Selen(Se)metabolismus wird von Hepatozyten gesteuert, die das Se-Transportprotein Selenoprotein P (SEPP) synthetisieren und sezernieren. SEPP nimmt bei kritischen Erkrankungen, z. B. Sepsis ab und führt zu niedrigen Se-Spiegeln. Sepsis triggert die übermäßige Produktion von proinflammatorischen Zytokinen. Aminoglykosid-Antibiotika (AG), die oft bei schwerer Sepsis eingesetzt werden, induzieren Fehlinterpretationen der mRNA inklusive des Stoppcodons UGA welches für die Selenoprotein-Biosynthese notwendig ist. Es wurden daher die molekularen Wechselwirkungen zwischen den Zytokinen IL-6, IL-1b und TNFa, AG und dem Se-Status mit der Biosynthese in Leberzelllinien untersucht. IL-6 führte zu einer starken Reduktion der SEPP-mRNA und einer dosisabhängigen Reduktion von SEPP. Parallel dazu reduzierte IL-6 das Transkriptlevel, die Proteinexpression und die Enzymaktivität der Typ-I-Dejodase (DIO1). Auf die Expression der antioxidativ-wirkenden Glutathionperoxidasen (GPX) wirkte IL-6 isozymspezifisch; während die Transkriptkonzentrationen von GPX2 anstiegen und die von GPX4 abnahmen, blieb GPX1 unbeeinflusst. Die IL-6-abhängigen Effekte bestätigten sich auch in Reportergenassays von SEPP-, DIO1-, GPX2- und GPX4-Promotorkonstrukten. Um die Wirkungen von AG auf die Selenoprotein-Translation besser zu verstehen, wurden die SECIS-Elemente von GPX1-, GPX4- und SEPP-Transkripten in ein Reportersystem kloniert und auf eine Regulation durch AG und Se analysiert. Die Ergebnisse zeigen, dass der korrekte Se-Einbau vom Se-Status, von der AG-Konzentration und dem spezifischen SECIS-Element abhängig ist. Auf transkriptionaler und translationaler Ebene führten AG zu stark erhöhten SEPP-Spiegeln, während die Expression und Enzymaktivität von GPX und DIO1 nur in geringerem Ausmaß beeinflusst wurden. Eine Analyse der Se-Beladung zeigte, dass der Se-Gehalt von SEPP stark durch AG reduziert und vom Se-Status abhängig war.
Selenoproteins play important roles in antioxidant defence and immunoregulation. Selenium (Se) metabolism is controlled by hepatocytes synthesizing and secreting the Se-transporter selenoprotein P (SEPP) declining in critical illness, e.g., sepsis. Sepsis triggers excessive production of pro-inflammatory cytokines. Aminoglycoside (AG) antibiotics applied in sepsis in induce mRNA misinterpretation including the stop codon UGA required during selenoproteins biosynthesis. The molecular interplay between the cytokines IL-6, IL-1b and TNFa, AG and Se-status on selenoprotein expression was investigated in hepatic-derived cell lines. IL-6 strongly reduced the level of SEPP mRNA and secreted SEPP in a dose-dependent manner. Likewise, expression of selenoenzyme type 1 deiodinase (DIO1) declined at the transcript, protein and enzyme activity level. The effects of IL-6 on the expression of antioxidative-acting glutathione peroxidases (GPX) were isozyme-specific; while transcript level of GPX2 increased and those of GPX4 decreased, GPX1 remained unaffected. IL-6-dependent effects were reflected in reporter gene experiments of selenoprotein promoter constructs. Characterising the effects of AG on selenoprotein translation, the SECIS-elements of GPX1, GPX4 and SEPP transcripts were cloned into a reporter system and analysed for their response to AG and Se. The results indicate that the correct co-translational Se-insertion depends on the Se-status, AG concentration and the specific SECIS-element. At both transcriptional and translational levels, SEPP levels were strongly increased in response to AG, whereas the expression and enzyme activity of GPX and DIO1 were affected to a lower degree. Analysis Se-status indicate that the Se-content of SEPP was strongly reduced by AG and depends on Se-status.
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50

Jakupoglu, Cemile. "Charakterisierung der Selenoproteine Thioredoxinreduktase 1 und 2 anhand von Knock-out-Mausmodellen". Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-13766.

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