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Vadim N Gladyshev - One of the best experts on this subject based on the ideXlab platform.
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Bioinformatics of Selenoproteins.
Antioxidants & Redox Signaling, 2020Co-Authors: Didac Santesmasses, Marco Mariotti, Vadim N GladyshevAbstract:Significance Bioinformatics has brought important insights into the field of selenium research. The progress made in the development of computational tools in the last two decades, coordinated with growing genome resources, provided new opportunities to study Selenoproteins. The present review discusses existing tools for Selenoprotein gene finding and other bioinformatic approaches to study the biology of selenium. Recent Advances The availability of complete selenoproteomes allowed assessing a global distribution of the use of selenocysteine across the tree of life, as well as studying the evolution of Selenoproteins and their biosynthetic pathway. Beyond gene identification and characterization, human genetic variants in Selenoprotein genes were used to examine adaptations to selenium levels in diverse human populations and to estimate selective constraints against gene loss. Critical Issues The synthesis of Selenoproteins is essential for development in mice. In humans, several mutations in Selenoprotein genes have been linked to rare congenital disorders. And yet, the mechanism of selenocysteine insertion and the regulation of Selenoprotein synthesis in mammalian cells are not completely understood. Future Directions Omics technologies offer new possibilities to study Selenoproteins and mechanisms of selenocysteine incorporation in cells, tissues and organisms.
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Selenoproteins in colon cancer
Free Radical Biology and Medicine, 2018Co-Authors: Kristin M. Peters, Bradley A Carlson, Vadim N Gladyshev, Petra A. TsujiAbstract:Abstract Selenocysteine-containing proteins (Selenoproteins) have been implicated in the regulation of various cell signaling pathways, many of which are linked to colorectal malignancies. In this in-depth excurse into the Selenoprotein literature, we review possible roles for human Selenoproteins in colorectal cancer, focusing on the typical hallmarks of cancer cells and their tumor-enabling characteristics. Human genome studies of single nucleotide polymorphisms in various genes coding for Selenoproteins have revealed potential involvement of glutathione peroxidases, thioredoxin reductases, and other proteins. Cell culture studies with targeted down-regulation of Selenoproteins and studies utilizing knockout/transgenic animal models have helped elucidate the potential roles of individual Selenoproteins in this malignancy. Those Selenoproteins, for which strong links to development or progression of colorectal cancer have been described, may be potential future targets for clinical interventions.
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Selenoprotein gene nomenclature
Journal of Biological Chemistry, 2016Co-Authors: Bradley A Carlson, Vadim N Gladyshev, Brigelius Flohe Regina, Elias S J Arner, Marla J Berry, Elspeth A Bruford, Raymond F Burk, Sergi Castellano, Laurent ChavatteAbstract:Abstract The human genome contains 25 genes coding for selenocysteine-containing proteins (Selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for Selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (Selenoprotein F, the 15 kDa Selenoprotein, SEP15), SELENOH (Selenoprotein H, SELH, C11orf31), SELENOI (Selenoprotein I, SELI, EPT1), SELENOK (Selenoprotein K, SELK), SELENOM (Selenoprotein M, SELM), SELENON (Selenoprotein N, SEPN1, SELN), SELENOO (Selenoprotein O, SELO), SELENOP (Selenoprotein P, SeP, SEPP1, SELP), SELENOS (Selenoprotein S, SELS, SEPS1, VIMP), SELENOT (Selenoprotein T, SELT), SELENOV (Selenoprotein V, SELV) and SELENOW (Selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for Selenoprotein genes and is applicable to Selenoproteins across vertebrates.
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Evolution of selenophosphate synthetases: Emergence and relocation of function through independent duplications and recurrent subfunctionalization
2015Co-Authors: Marco Mariotti, Montserrat Corominas, Florenci Serras, Didac Santesmasses, Salvador Capella-Gutierrez, Andrea Mateo, Carme Arnan, Salvatore D'Aniello, Sun Hee Yim, Toni Gabald??n, Rory Johnson, Vadim N Gladyshev, Roderic Guig??Abstract:Abstract SPS catalyzes the synthesis of selenophosphate, the selenium donor for the synthesis of the amino acid selenocysteine (Sec), incorporated in Selenoproteins in response to the UGA codon. SPS is unique among proteins of the Selenoprotein biosynthesis machinery in that it is, in many species, a Selenoprotein itself, although, as in all Selenoproteins, Sec is often replaced by cysteine (Cys). In metazoan genomes we found, however, SPS genes with lineage specific substitutions other than Sec or Cys. Our results show that these non-Sec, non-Cys SPS genes originated through a number of independent gene duplications of diverse molecular origin from an ancestral Selenoprotein SPS gene. Although of independent origin, complementation assays in fly mutants show that these genes share a common function, which most likely emerged in the ancestral metazoan gene. This function appears to be unrelated to selenophosphate synthesis, since all genomes encoding Selenoproteins contain Sec or Cys SPS genes (SPS2), but those containing only non-Sec, non-Cys SPS genes (SPS1) do not encode Selenoproteins. Thus, in SPS genes, through parallel duplications and subsequent convergent subfunctionalization, two functions initially carried by a single gene are recurrently segregated at two different loci. RNA structures enhancing the readthrough of the Sec-UGA codon in SPS genes, which may be traced back to prokaryotes, played a key role in this process. The SPS evolutionary history in metazoans constitute a remarkable example of the emergence and evolution of gene function. We have been able to trace this history with unusual detail thanks to the singular feature of SPS genes, wherein the amino acid at a single site determines protein function, and, ultimately, the evolutionary fate of an entire class of genes.
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Regulation of selenocysteine content of human Selenoprotein p by dietary selenium and insertion of cysteine in place of selenocysteine
2015Co-Authors: A. A. Turanov, Robert A. Everley, Sandra Hybsier, Kostja Renko, Lutz Schomburg, Dolph L Hatfield, Stephen P. Gygi, Vadim N GladyshevAbstract:Selenoproteins are a unique group of proteins that contain selenium in the form of selenocysteine (Sec) co-translationally inserted in response to a UGA codon with the help of cis- and trans-acting factors. Mammalian Selenoproteins contain single Sec residues, with the exception of Selenoprotein P (SelP) that has 7-15 Sec residues depending on species. Assessing an individual's selenium status is important under various pathological conditions, which requires a reliable selenium biomarker. Due to a key role in organismal selenium homeostasis, high Sec content, regulation by dietary selenium, and availability of robust assays in human plasma, SelP has emerged as a major biomarker of selenium status. Here, we found that Cys is present in various Sec positions in human SelP. Treatment of cells expressing SelP with thiophosphate, an analog of the selenium donor for Sec synthesis, led to a nearly complete replacement of Sec with Cys, whereas supplementation of cells with selenium supported Sec insertion. SelP isolated directly from human plasma had up to 8% Cys inserted in place of Sec, depending on the Sec position. These findings suggest that a change in selenium status may be reflected in both SelP concentration and its Sec content, and that availability of the SelP-derived selenium for Selenoprotein synthesis may be overestimated under conditions of low selenium status due to replacement of Sec with Cys.
Dolph L Hatfield - One of the best experts on this subject based on the ideXlab platform.
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Models for assessing the role of Selenoproteins in health.
The Journal of nutrition, 2020Co-Authors: Mohamed E Moustafa, Nianxin Zhong, Easwari Kumaraswamy, Bradley A Carlson, Dolph L HatfieldAbstract:Two model systems for examining the role of Selenoproteins in health are discussed. One utilizes transgenic mice that carry mutant selenocysteine (Sec) tRNA transgenes that result in the reduction of Selenoprotein expression in a protein- and tissue-specific manner. The other utilizes loxP-Cre technology to selectively remove the Sec tRNA gene in mammary epithelium that results in the reduction of only certain Selenoproteins in this tissue. Both approaches provide important tools for examining the role of Selenoproteins in health.
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Regulation of selenocysteine content of human Selenoprotein p by dietary selenium and insertion of cysteine in place of selenocysteine
2015Co-Authors: A. A. Turanov, Robert A. Everley, Sandra Hybsier, Kostja Renko, Lutz Schomburg, Dolph L Hatfield, Stephen P. Gygi, Vadim N GladyshevAbstract:Selenoproteins are a unique group of proteins that contain selenium in the form of selenocysteine (Sec) co-translationally inserted in response to a UGA codon with the help of cis- and trans-acting factors. Mammalian Selenoproteins contain single Sec residues, with the exception of Selenoprotein P (SelP) that has 7-15 Sec residues depending on species. Assessing an individual's selenium status is important under various pathological conditions, which requires a reliable selenium biomarker. Due to a key role in organismal selenium homeostasis, high Sec content, regulation by dietary selenium, and availability of robust assays in human plasma, SelP has emerged as a major biomarker of selenium status. Here, we found that Cys is present in various Sec positions in human SelP. Treatment of cells expressing SelP with thiophosphate, an analog of the selenium donor for Sec synthesis, led to a nearly complete replacement of Sec with Cys, whereas supplementation of cells with selenium supported Sec insertion. SelP isolated directly from human plasma had up to 8% Cys inserted in place of Sec, depending on the Sec position. These findings suggest that a change in selenium status may be reflected in both SelP concentration and its Sec content, and that availability of the SelP-derived selenium for Selenoprotein synthesis may be overestimated under conditions of low selenium status due to replacement of Sec with Cys.
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understanding Selenoprotein function and regulation through the use of rodent models
Biochimica et Biophysica Acta, 2012Co-Authors: Marina V Kasaikina, Dolph L Hatfield, Vadim N GladyshevAbstract:Abstract Selenium (Se) is an essential micronutrient. Its biological functions are associated with Selenoproteins, which contain this trace element in the form of the 21st amino acid, selenocysteine. Genetic defects in selenocysteine insertion into proteins are associated with severe health issues. The consequences of Selenoprotein deficiency are more variable, with several Selenoproteins being essential, and several showing no clear phenotypes. Much of these functional studies benefited from the use of rodent models and diets employing variable levels of Se. This review summarizes the data obtained with these models, focusing on mouse models with targeted expression of individual Selenoproteins and removal of individual, subsets or all Selenoproteins in a systemic or organ-specific manner. This article is part of a Special Issue entitled: Cell Biology of Metals.
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Analyses of fruit flies that do not express Selenoproteins or express the mouse Selenoprotein, methionine sulfoxide reductase B1,reveal a role of Selenoproteins in stress resistance
2011Co-Authors: Valentina A. Shchedrina, Byeong Jae Lee, Hadise Kabil, Gerd Vorbruggen, A. A. Turanov, Lawrence G. Harshman, Mitsuko Hirosawa-Takamori, Dolph L Hatfield, Hwa Young Kim, Vadim N GladyshevAbstract:Selenoproteins are essential in vertebrates because of their crucial role in cellular redox homeostasis, but some invertebrates that lack Selenoproteins have recently been identified. Genetic disruption of Selenoprotein biosynthesis had no effect on lifespan and oxidative stress resistance of Drosophila melanogaster. In the current study, fruit flies with knock-out of the selenocysteine-specific elongation factor were metabolically labeled with (75)Se; they did not incorporate selenium into proteins and had the same lifespan on a chemically defined diet with or without selenium supplementation. These flies were, however, more susceptible to starvation than controls, and this effect could be ascribed to the function of Selenoprotein K. We further expressed mouse methionine sulfoxide reductase B1 (MsrB1), a selenoenzyme that catalyzes the reduction of oxidized methionine residues and has protein repair function, in the whole body or the nervous system of fruit flies. This exogenous Selenoprotein could only be expressed when the Drosophila selenocysteine insertion sequence element was used, whereas the corresponding mouse element did not support Selenoprotein synthesis. Ectopic expression of MsrB1 in the nervous system led to an increase in the resistance against oxidative stress and starvation, but did not affect lifespan and reproduction, whereas ubiquitous MsrB1 expression had no effect. Dietary selenium did not influence lifespan of MsrB1-expressing flies. Thus, in contrast to vertebrates, fruit flies preserve only three Selenoproteins, which are not essential and play a role only under certain stress conditions, thereby limiting the use of the micronutrient selenium by these organisms.
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Selenoprotein T deficiency alters cell adhesion and elevates Selenoprotein W expression in murine fibroblast cells
Biochemistry and Cell Biology, 2009Co-Authors: Aniruddha Sengupta, Bradley A Carlson, Vadim N Gladyshev, Vyacheslav M. Labunskyy, Dolph L HatfieldAbstract:Mammalian Selenoproteins have diverse functions, cellular locations, and evolutionary histories, but all use the amino acid selenocysteine (Sec), often present in the enzyme’s active site. Only about half of mammalian Selenoproteins have been functionally characterized, with most being oxidoreductases. The cellular role of Selenoprotein T (SelT), manifesting a CxxU motif in a thioredoxin-like fold and localized to Golgi and the endoplasmic reticulum, is not known. To examine its biological function, we knocked down SelT expression in mouse fibroblast cells and found that SelT deficiency alters cell adhesion and enhances the expression of several oxidoreductase genes, while decreasing the expression of genes involved in cell structure organization, suggesting the involvement of SelT in redox regulation and cell anchorage. Furthermore, we found that the loss of SelT elevates expression of another Selenoprotein, Selenoprotein W (SepW1). SelT and SepW1 belong to the same protein family, suggesting that SepW1 ...
John E Hesketh - One of the best experts on this subject based on the ideXlab platform.
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the influence of selenium and Selenoprotein gene variants on colorectal cancer risk
Mutagenesis, 2012Co-Authors: Catherine Meplan, John E HeskethAbstract:Colorectal cancer (CRC) is a major cause of mortality throughout the world and risk of CRC is known to be modulated by nutritional factors. Low intake of the micronutrient selenium (Se) has been implicated as a risk factor in CRC, and in this article we describe the biochemical functions of selenium in Selenoproteins, review the evidence for an association of selenium status with CRC and adenoma risk and describe the genetic epidemiological data on Selenoprotein genes and CRC risk. Epidemiological evidence linking Se intake to CRC risk is limited but there is strong evidence for a link to adenoma risk. Two studies show an association between a genetic variant in the Selenoprotein S gene and CRC risk. Selenium intake modulates Selenoprotein expression in the colon, especially Selenoproteins W, H, M, 15 kDa Selenoprotein and glutathione peroxidase 1, and downstream targets such as endoplasmic reticulum stress response, oxidative stress and inflammatory pathways. We hypothesis that Se, through the Selenoproteins, plays a key role in the ability of colonic epithelial cells to respond to microbial and oxidative challenges and that a combination of low Se intake and SNP in Selenoprotein genes can impair that role and so lead to increased risk of pre-neoplastic lesions. There is a need for both further studies of Selenoprotein function in the colon and major genetic epidemiological and intervention studies.
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polymorphisms in the Selenoprotein s and 15 kda Selenoprotein genes are associated with altered susceptibility to colorectal cancer
Genes and Nutrition, 2010Co-Authors: Alison Sutherland, Caroline L Relton, John E HeskethAbstract:Selenium (Se), a dietary trace metal essential for human health, is incorporated into ~25 Selenoproteins including Selenoprotein S (SelS) and the 15-kDa Selenoprotein (Sep15) both of which have functions in the endoplasmic reticulum protein unfolding response. The aim of this study was to investigate whether genetic variants in such Selenoprotein genes are associated with altered risk of colorectal cancer (CRC). A Korean population of 827 patients with CRC and 733 healthy controls was genotyped for 7 SNPs in Selenoprotein genes and one SNP in the gene encoding manganese superoxide dismutase using Sequenom technology. Multivariate logistic regression analysis showed that after adjustment for lifestyle factors three SNP variants were associated with altered disease risk. There was a mean odds ratio of 2.25 [95% CI 1.13,4.48] in females homozygous TT for rs34713741 in SELS with the T variant being associated with higher risk of rectal cancer, and odds ratios of 2.47 and 2.51, respectively, for rs5845 and rs5859 in SEP15 with the minor A and T alleles being associated with increased risk of male rectal cancer. The data indicate that the minor alleles for rs5845, rs5859 and rs34713741 are associated with increased rectal cancer risk and that the effects of the three SNPs are dependent on gender. The results highlight potential links between Se, the function of two Selenoproteins involved in the protein unfolding response and CRC risk. Further studies are required to investigate whether the effects of the variants on CRC risk are also modulated by dietary Se intake.
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Selenoprotein gene expression during selenium-repletion of selenium-deficient rats
Biological Trace Element Research, 1996Co-Authors: Giovanna Bermano, Roger A. Sunde, Fergus Nicol, John A. Dyer, Geoffrey J. Beckett, John R. Arthur, John E HeskethAbstract:Selenium repletion of selenium-deficient rats with 20 μg selenium/kg body weight as Na_2SeO_3 was used as a model to investigate the mechanisms that control the distribution of the trace element to specific Selenoproteins in liver and thyroid. Cytosolic glutathione peroxidase (cGSHPx), phospholipid hydroperoxide glutathione peroxidase (PHGSHPx), and iodothyronine 5′-deiodinase (IDI) activities were all transiently increased in liver 16 to 32 h after ip injection with selenium. However, only cGSHPx and PHGSHPx activities increased in the thyroid where IDI activity was already increased by selenium deficiency. These responses were owing to synthesis of the seleoproteins on newly synthesised and/or existing mRNAs. The Selenoprotein mRNAs in the thyroid gland were increased two- and threefold after the transitory increases in Selenoprotein activity. In contrast, there were parallel changes in Selenoprotein mRNAs and enzyme activities in the liver, with no prolonged rises in mRNA levels. The organ differences suggest that increased thryotrophin (TSH) concentrations, which are known to induce thyrodial IDI and mRNA, may control the mRNAs for all the thyroidal Selenoproteins investigated and be a major mechanism for the preservation of thyroidal Selenoproteins when selenium supplies are limited.
Bradley A Carlson - One of the best experts on this subject based on the ideXlab platform.
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Models for assessing the role of Selenoproteins in health.
The Journal of nutrition, 2020Co-Authors: Mohamed E Moustafa, Nianxin Zhong, Easwari Kumaraswamy, Bradley A Carlson, Dolph L HatfieldAbstract:Two model systems for examining the role of Selenoproteins in health are discussed. One utilizes transgenic mice that carry mutant selenocysteine (Sec) tRNA transgenes that result in the reduction of Selenoprotein expression in a protein- and tissue-specific manner. The other utilizes loxP-Cre technology to selectively remove the Sec tRNA gene in mammary epithelium that results in the reduction of only certain Selenoproteins in this tissue. Both approaches provide important tools for examining the role of Selenoproteins in health.
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Selenoproteins in colon cancer
Free Radical Biology and Medicine, 2018Co-Authors: Kristin M. Peters, Bradley A Carlson, Vadim N Gladyshev, Petra A. TsujiAbstract:Abstract Selenocysteine-containing proteins (Selenoproteins) have been implicated in the regulation of various cell signaling pathways, many of which are linked to colorectal malignancies. In this in-depth excurse into the Selenoprotein literature, we review possible roles for human Selenoproteins in colorectal cancer, focusing on the typical hallmarks of cancer cells and their tumor-enabling characteristics. Human genome studies of single nucleotide polymorphisms in various genes coding for Selenoproteins have revealed potential involvement of glutathione peroxidases, thioredoxin reductases, and other proteins. Cell culture studies with targeted down-regulation of Selenoproteins and studies utilizing knockout/transgenic animal models have helped elucidate the potential roles of individual Selenoproteins in this malignancy. Those Selenoproteins, for which strong links to development or progression of colorectal cancer have been described, may be potential future targets for clinical interventions.
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Radioactive 75 Se Labeling and Detection of Selenoproteins
Methods in molecular biology (Clifton N.J.), 2017Co-Authors: Ryuta Tobe, Anton A. Turanov, Bradley A CarlsonAbstract:The trace element selenium (Se) is incorporated into proteins as the amino acid selenocysteine (Sec), which is cotranslationally inserted into specific proteins in response to a UGA codon. Proteins containing Sec at these specific positions are called Selenoproteins. Most Selenoproteins function as oxidoreductases, while some serve other important functions. There are 25 known Selenoprotein genes in humans and 24 in mice. The use of Sec allows Selenoproteins to be detected by a convenient method involving metabolic labeling with 75Se. Labeling of cells and whole animals are used for the examination of Selenoprotein expression profiles and the investigation of Selenoprotein functions. In mammals, nonspecific 75Se insertion is very low, and sensitivity and specificity of Selenoprotein detection approaches that of Western blotting. This method allows for the examination of Selenoprotein expression and Se metabolism in model and non-model organisms. Herein, we describe experimental protocols for analyzing Selenoproteins by metabolic labeling with 75Se both in vitro and in vivo. As an example, the procedure for metabolic labeling of HEK293T human embryonic kidney cells is described in detail. This approach remains a method of choice for the detection of Selenoproteins in diverse settings.
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Selenoprotein gene nomenclature
Journal of Biological Chemistry, 2016Co-Authors: Bradley A Carlson, Vadim N Gladyshev, Brigelius Flohe Regina, Elias S J Arner, Marla J Berry, Elspeth A Bruford, Raymond F Burk, Sergi Castellano, Laurent ChavatteAbstract:Abstract The human genome contains 25 genes coding for selenocysteine-containing proteins (Selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for Selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (Selenoprotein F, the 15 kDa Selenoprotein, SEP15), SELENOH (Selenoprotein H, SELH, C11orf31), SELENOI (Selenoprotein I, SELI, EPT1), SELENOK (Selenoprotein K, SELK), SELENOM (Selenoprotein M, SELM), SELENON (Selenoprotein N, SEPN1, SELN), SELENOO (Selenoprotein O, SELO), SELENOP (Selenoprotein P, SeP, SEPP1, SELP), SELENOS (Selenoprotein S, SELS, SEPS1, VIMP), SELENOT (Selenoprotein T, SELT), SELENOV (Selenoprotein V, SELV) and SELENOW (Selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for Selenoprotein genes and is applicable to Selenoproteins across vertebrates.
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secisbp2 is essential for embryonic development and enhances Selenoprotein expression
Antioxidants & Redox Signaling, 2014Co-Authors: Bradley A Carlson, Sandra Seeher, Yassin Mahdi, Doreen Braun, Tarik Atassi, Eva K Wirth, M KleinAbstract:Abstract Aims: The selenocysteine insertion sequence (SECIS)-binding protein 2 (Secisbp2) binds to SECIS elements located in the 3′-untranslated region of eukaryotic Selenoprotein mRNAs. Selenoproteins contain the rare amino acid selenocysteine (Sec). Mutations in SECISBP2 in humans lead to reduced Selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display myopathy, hearing impairment, male infertility, increased photosensitivity, mental retardation, and ataxia. Mouse models are needed to understand Selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes. Results: Unlike tRNA[Ser]Sec-deficient embryos, homozygous Secisbp2-deleted embryos implant, but fail before gastrulation. Heterozygous inactivation of Secisbp2 reduced the amount of Selenoprotein expressed, but did not affect the thyroid hormone axis or growth. Conditional deletion of Secisbp2 in hepatocytes significantly decreased Selenoprotein ...
M J Berry - One of the best experts on this subject based on the ideXlab platform.
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Mice lacking Selenoprotein P and selenocysteine lyase exhibit severe neurological dysfunction, neurodegeneration, and audiogenic seizures
2014Co-Authors: China N. Byrns, a. C. Hashimoto, Christy A. Gilman, M W Pitts, M J BerryAbstract:Selenoproteins are a unique family of proteins, characterized by the co-translational incorporation of selenium as selenocysteine, which play key roles in antioxidant defense. Among Selenoproteins, Selenoprotein P (Sepp1) is particularly distinctive due to the fact that it contains multiple selenocysteine residues and has been postulated to act in selenium transport. Within the brain, Sepp1 delivers selenium to neurons by binding to the ApoER2 receptor. Upon feeding a selenium-deficient diet, mice lacking ApoER2 or Sepp1 develop severe neurological dysfunction and exhibit widespread brainstem neurodegeneration, indicating an important role for ApoER2-mediated Sepp1 uptake in normal brain function. Selenocysteine lyase (Scly) is an enzyme that plays an important role in selenium homeostasis, in that it catalyzes the decomposition of selenocysteine and allows selenium to be recycled for additional Selenoprotein synthesis. We previously reported that constitutive deletion of Scly results in neurological deficits only when mice are challenged with a low selenium diet. To gain insight into the relationship between Sepp1 and Scly in selenium metabolism, we created novel transgenic mice constitutively lacking both genes (Scly-/-Sepp1-/-) and characterized the neurobehavioral phenotype. We report that deletion of Scly in conjunction with Sepp1 further aggravates the phenotype of Sepp1-/- mice, as these mice needed supraphysiological selenium supplementation to survive, and surviving mice exhibited impaired motor coordination, audiogenic seizures, and brainstem neurodegeneration. These findings provide the first in vivo evidence that Scly and Sepp1 work cooperatively to maintain Selenoprotein function in the mammalian brain.
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Effects of acclimation salinity on the expression of Selenoproteins in the tilapia, Oreochromis mossambicus
2014Co-Authors: Lucia A. Seale, M J Berry, Christy A. Gilman, Benjamin P. Moorman, E. Gordon Grau, Andre P. SealeAbstract:Selenoproteins are ubiquitously expressed, act on a variety of physiological redox-related processes, and are mostly regulated by selenium levels in animals. To date, the expression of most Selenoproteins has not been verified in euryhaline fish models. The Mozambique tilapia, Oreochromis mossambicus, a euryhaline cichlid fish, has a high tolerance for changes in salinity and survives in fresh water (FW) and seawater (SW) environments which differ greatly in selenium availability. In the present study, we searched EST databases for cichlid Selenoprotein mRNAs and screened for their differential expression in FW and SW-acclimated tilapia. The expression of mRNAs encoding iodothyronine deiodinases 1, 2 and 3 (Dio1, Dio2, Dio3), Fep15, glutathione peroxidase 2, Selenoproteins J, K, L, M, P, S, and W, was measured in the brain, eye, gill, kidney, liver, pituitary, muscle, and intraperitoneal white adipose tissue. Gene expression of selenophosphate synthetase 1, Secp43, and selenocysteine lyase, factors involved in Selenoprotein synthesis or in selenium metabolism, were also measured. The highest variation in Selenoprotein and synthesis factor mRNA expression between FW- and SW-acclimated fish was found in gill and kidney. While the branchial expression of Dio3 was increased upon transferring tilapia from SW to FW, the inverse effect was observed when fish were transferred from FW to SW. Protein content of Dio3 was higher in fish acclimated to FW than in those acclimated to SW. Together, these results outline tissue distribution of Selenoproteins in FW and SW-acclimated tilapia, and indicate that at least Dio3 expression is regulated by environmental salinity. ?? 2014 Elsevier GmbH.
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Changes in Selenoprotein P in substantia nigra and putamen in Parkinson's disease
2012Co-Authors: Frederick P. Bellinger, Rachel H. Rueli, Miyoko T. Bellinger, Andrea S. Dewing, Marilou A. Andres, Jane H. Uyehara-Lock, Lon R. White, G. Webster Ross, Lucia A. Seale, Arjun V. Raman, M J BerryAbstract:Oxidative stress and oxidized dopamine contribute to the degeneration of the nigrostriatal pathway in Parkinson's disease (PD). Selenoproteins are a family of proteins containing the element selenium in the form of the amino acid selenocysteine, and many of these proteins have antioxidant functions. We recently reported changes in expression of the Selenoprotein, phospholipid hydroperoxide glutathione peroxidase GPX4 and its co-localization with neuromelanin in PD brain. To further understand the changes in GPX4 in PD, we examine here the expression of the selenium transport protein Selenoprotein P (Sepp1) in postmortem Parkinson's brain tissue. Sepp1 in midbrain was expressed in neurons of the substantia nigra (SN), and expression was concentrated within the centers of Lewy bodies, the pathological hallmark of PD. As with GPX4, Sepp1 expression was significantly reduced in SN from PD subjects compared with controls, but increased relative to cell density. In putamen, Sepp1 was found in cell bodies and in dopaminergic axons and terminals, although levels of Sepp1 were not altered in PD subjects compared to controls. Expression levels of Sepp1 and GPX4 correlated strongly in the putamen of control subjects but not in the putamen of PD subjects. These findings indicate a role for Sepp1 in the nigrostriatal pathway, and suggest that local release of Sepp1 in striatum may be important for signaling and/or synthesis of other Selenoproteins such as GPX4.
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Disruption of the Selenocysteine Lyase-Mediated Selenium Recycling Pathway Leads to Metabolic Syndrome in Mice
2012Co-Authors: Lucia A. Seale, a. C. Hashimoto, Suguru Kurokawa, C. L. Gilman, Ali Seyedali, Frederick P. Bellinger, Arjun V. Raman, M J BerryAbstract:Selenium (Se) is an essential trace element used for biosynthesis of Selenoproteins and is acquired either through diet or cellular recycling mechanisms. Selenocysteine lyase (Scly) is the enzyme that supplies Se for Selenoprotein biosynthesis via decomposition of the amino acid selenocysteine (Sec). Knockout (KO) of Scly in a mouse affected hepatic glucose and lipid homeostasis. Mice lacking Scly and raised on an Se-adequate diet exhibit hyperinsulinemia, hyperleptinemia, glucose intolerance, and hepatic steatosis, with increased hepatic oxidative stress, but maintain Selenoprotein levels and circulating Se status. Insulin challenge of Scly KO mice results in attenuated Akt phosphorylation but does not decrease phosphorylation levels of AMP kinase alpha (AMPK?). Upon dietary Se restriction, Scly KO animals develop several characteristics of metabolic syndrome, such as obesity, fatty liver, and hypercholesterolemia, with aggravated hyperleptinemia, hyperinsulinemia, and glucose intolerance. Hepatic glutathione peroxidase 1 (GPx1) and Selenoprotein S (SelS) production and circulating Selenoprotein P (Sepp1) levels are significantly diminished. Scly disruption increases the levels of insulin-signaling inhibitor PTP1B. Our results suggest a dependence of glucose and lipid homeostasis on Scly activity. These findings connect Se and energy metabolism and demonstrate for the first time a unique physiological role of Scly in an animal model.
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Transcriptional regulation of mammalian Selenoprotein expression
2009Co-Authors: Zoia R. Stoytcheva, M J BerryAbstract:Background: Selenoproteins contain the twenty-first amino acid, selenocysteine, and are involved in cellular defenses against oxidative damage, important metabolic and developmental pathways, and responses to environmental challenges. Elucidating the mechanisms regulating Selenoprotein expression at the transcriptional level is a key to understanding how these mechanisms are called into play to respond to the changing environment. Methods: This review summarizes published studies on transcriptional regulation of Selenoprotein genes, focused primarily on genes whose encoded protein functions are at least partially understood. This is followed by in silico analysis of predicted regulatory elements in Selenoprotein genes, including those in the aforementioned category as well as the genes whose functions are not known. Results: Our findings reveal regulatory pathways common to many Selenoprotein genes, including several involved in stress-responses. In addition, tissue-specific regulatory factors are implicated in regulating many Selenoprotein genes. Conclusions: These studies provide new insights into how Selenoprotein genes respond to environmental and other challenges, and the roles these proteins play in allowing cells to adapt to these changes. General significance: Elucidating the regulatory mechanisms affecting Selenoprotein expression is essential for understanding their roles in human diseases, and for developing diagnostic and potential therapeutic approaches to address dysregulation of members of this gene family. ?? 2009 Elsevier B.V. All rights reserved.
