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Selenoproteins in Tumorigenesis and Cancer Progression.
Short SP, Williams CS
(2017) Adv Cancer Res 136: 49-83
MeSH Terms: Animals, Antioxidants, Carcinogenesis, Disease Progression, Humans, Neoplasms, Oxidation-Reduction, Oxidative Stress, Selenium, Selenoproteins
Show Abstract · Added April 15, 2019
Selenium is a micronutrient essential to human health and has long been associated with cancer prevention. Functionally, these effects are thought to be mediated by a class of selenium-containing proteins known as selenoproteins. Indeed, many selenoproteins have antioxidant activity which can attenuate cancer development by minimizing oxidative insult and resultant DNA damage. However, oxidative stress is increasingly being recognized for its "double-edged sword" effect in tumorigenesis, whereby it can mediate both negative and positive effects on tumor growth depending on the cellular context. In addition to their roles in redox homeostasis, recent work has also implicated selenoproteins in key oncogenic and tumor-suppressive pathways. Together, these data suggest that the overall contribution of selenoproteins to tumorigenesis is complicated and may be affected by a variety of factors. In this review, we discuss what is currently known about selenoproteins in tumorigenesis with a focus on their contextual roles in cancer development, growth, and progression.
© 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
Regulation of Selenium Metabolism and Transport.
Burk RF, Hill KE
(2015) Annu Rev Nutr 35: 109-34
MeSH Terms: Animals, Biological Availability, Biological Transport, Biomarkers, Diet, Dietary Supplements, Health Status, Homeostasis, Humans, Kidney Tubules, Proximal, LDL-Receptor Related Proteins, Liver, Low Density Lipoprotein Receptor-Related Protein-2, Nutritional Requirements, Organ Specificity, Selenium, Selenocysteine, Selenomethionine, Selenoprotein P, Selenoproteins
Show Abstract · Added September 28, 2015
Selenium is regulated in the body to maintain vital selenoproteins and to avoid toxicity. When selenium is limiting, cells utilize it to synthesize the selenoproteins most important to them, creating a selenoprotein hierarchy in the cell. The liver is the central organ for selenium regulation and produces excretory selenium forms to regulate whole-body selenium. It responds to selenium deficiency by curtailing excretion and secreting selenoprotein P (Sepp1) into the plasma at the expense of its intracellular selenoproteins. Plasma Sepp1 is distributed to tissues in relation to their expression of the Sepp1 receptor apolipoprotein E receptor-2, creating a tissue selenium hierarchy. N-terminal Sepp1 forms are taken up in the renal proximal tubule by another receptor, megalin. Thus, the regulated whole-body pool of selenium is shifted to needy cells and then to vital selenoproteins in them to supply selenium where it is needed, creating a whole-body selenoprotein hierarchy.
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20 MeSH Terms
Sepp1(UF) forms are N-terminal selenoprotein P truncations that have peroxidase activity when coupled with thioredoxin reductase-1.
Kurokawa S, Eriksson S, Rose KL, Wu S, Motley AK, Hill S, Winfrey VP, McDonald WH, Capecchi MR, Atkins JF, Arnér ES, Hill KE, Burk RF
(2014) Free Radic Biol Med 69: 67-76
MeSH Terms: Animals, Biological Transport, Endocytosis, Glutathione Peroxidase, Hydrogen Peroxide, Kidney Glomerulus, Kidney Tubules, Proximal, Mice, Oxidation-Reduction, Protein Structure, Tertiary, Selenocysteine, Selenoproteins, Thioredoxin Reductase 1
Show Abstract · Added March 10, 2014
Mouse selenoprotein P (Sepp1) consists of an N-terminal domain (residues 1-239) that contains one selenocysteine (U) as residue 40 in a proposed redox-active motif (-UYLC-) and a C-terminal domain (residues 240-361) that contains nine selenocysteines. Sepp1 transports selenium from the liver to other tissues by receptor-mediated endocytosis. It also reduces oxidative stress in vivo by an unknown mechanism. A previously uncharacterized plasma form of Sepp1 is filtered in the glomerulus and taken up by renal proximal convoluted tubule (PCT) cells via megalin-mediated endocytosis. We purified Sepp1 forms from the urine of megalin(-/-) mice using a monoclonal antibody to the N-terminal domain. Mass spectrometry revealed that the purified urinary Sepp1 consisted of N-terminal fragments terminating at 11 sites between residues 183 and 208. They were therefore designated Sepp1(UF). Because the N-terminal domain of Sepp1 has a thioredoxin fold, Sepp1(UF) were compared with full-length Sepp1, Sepp1(Δ240-361), and Sepp1(U40S) as a substrate of thioredoxin reductase-1 (TrxR1). All forms of Sepp1 except Sepp1(U40S), which contains serine in place of the selenocysteine, were TrxR1 substrates, catalyzing NADPH oxidation when coupled with H2O2 or tert-butylhydroperoxide as the terminal electron acceptor. These results are compatible with proteolytic cleavage freeing Sepp1(UF) from full-length Sepp1, the form that has the role of selenium transport, allowing Sepp1(UF) to function by itself as a peroxidase. Ultimately, plasma Sepp1(UF) and small selenium-containing proteins are filtered by the glomerulus and taken up by PCT cells via megalin-mediated endocytosis, preventing loss of selenium in the urine and providing selenium for the synthesis of glutathione peroxidase-3.
Copyright © 2014 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Polymorphisms in the Selenoprotein S gene and subclinical cardiovascular disease in the Diabetes Heart Study.
Cox AJ, Lehtinen AB, Xu J, Langefeld CD, Freedman BI, Carr JJ, Bowden DW
(2013) Acta Diabetol 50: 391-9
MeSH Terms: Aged, Cardiovascular Diseases, Carotid Artery Diseases, Carotid Intima-Media Thickness, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Female, Genotype, Humans, Introns, Linkage Disequilibrium, Male, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Selenoproteins, Vascular Calcification
Show Abstract · Added February 15, 2014
Selenoprotein S (SelS) has previously been associated with a range of inflammatory markers, particularly in the context of cardiovascular disease (CVD). The aim of this study was to examine the role of SELS genetic variants in risk for subclinical CVD and mortality in individuals with type 2 diabetes mellitus (T2DM). The association between 10 polymorphisms tagging SELS and coronary (CAC), carotid (CarCP) and abdominal aortic calcified plaque, carotid intima media thickness and other known CVD risk factors was examined in 1220 European Americans from the family-based Diabetes Heart Study. The strongest evidence of association for SELS SNPs was observed for CarCP; rs28665122 (5' region; β = 0.329, p = 0.044), rs4965814 (intron 5; β = 0.329, p = 0.036), rs28628459 (3' region; β = 0.331, p = 0.039) and rs7178239 (downstream; β = 0.375, p = 0.016) were all associated. In addition, rs12917258 (intron 5) was associated with CAC (β = -0.230, p = 0.032), and rs4965814, rs28628459 and rs9806366 were all associated with self-reported history of prior CVD (p = 0.020-0.043). These results suggest a potential role for the SELS region in the development subclinical CVD in this sample enriched for T2DM. Further understanding the mechanisms underpinning these relationships may prove important in predicting and managing CVD complications in T2DM.
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18 MeSH Terms
Long isoform mouse selenoprotein P (Sepp1) supplies rat myoblast L8 cells with selenium via endocytosis mediated by heparin binding properties and apolipoprotein E receptor-2 (ApoER2).
Kurokawa S, Hill KE, McDonald WH, Burk RF
(2012) J Biol Chem 287: 28717-26
MeSH Terms: Animals, Cell Line, Chlorates, Endocytosis, Glutathione Peroxidase, LDL-Receptor Related Proteins, Lysosomes, Mice, Mice, Knockout, Myoblasts, Protein Isoforms, Rats, Receptors, LDL, Selenoproteins, Tumor Suppressor Proteins
Show Abstract · Added March 7, 2014
In vivo studies have shown that selenium is supplied to testis and brain by apoER2-mediated endocytosis of Sepp1. Although cultured cell lines have been shown to utilize selenium from Sepp1 added to the medium, the mechanism of uptake and utilization has not been characterized. Rat L8 myoblast cells were studied. They took up mouse Sepp1 from the medium and used its selenium to increase their glutathione peroxidase (Gpx) activity. L8 cells did not utilize selenium from Gpx3, the other plasma selenoprotein. Neither did they utilize it from Sepp1(Δ240-361), the isoform of Sepp1 that lacks the selenium-rich C-terminal domain. To identify Sepp1 receptors, a solubilized membrane fraction was passed over a Sepp1 column. The receptors apoER2 and Lrp1 were identified in the eluate by mass spectrometry. siRNA experiments showed that knockdown of apoER2, but not of Lrp1, inhibited (75)Se uptake from (75)Se-labeled Sepp1. The addition of protamine to the medium or treatment of the cells with chlorate also inhibited (75)Se uptake. Blockage of lysosome acidification did not inhibit uptake of Sepp1 but did prevent its digestion and thereby utilization of its selenium. These results indicate that L8 cells take up Sepp1 by an apoER2-mediated mechanism requiring binding to heparin sulfate proteoglycans. The presence of at least part of the selenium-rich C-terminal domain of Sepp1 is required for uptake. RT-PCR showed that mouse tissues express apoER2 in varying amounts. It is postulated that apoER2-mediated uptake of long isoform Sepp1 is responsible for selenium distribution to tissues throughout the body.
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15 MeSH Terms
Selenoprotein P: an extracellular protein with unique physical characteristics and a role in selenium homeostasis.
Burk RF, Hill KE
(2005) Annu Rev Nutr 25: 215-35
MeSH Terms: Amino Acid Sequence, Animals, Dietary Supplements, Glycosylation, Heparin, Homeostasis, Humans, Mercury, Molecular Sequence Data, Protein Isoforms, Proteins, Selenium, Selenoprotein P, Selenoproteins
Show Abstract · Added March 5, 2014
Selenoprotein P is an abundant extracellular glycoprotein that is rich in selenocysteine. It has two domains with respect to selenium content. The N-terminal domain of the rat protein contains one selenocysteine residue in a UxxC redox motif. This domain also has a pH-sensitive heparin-binding site and two histidine-rich amino acid stretches. The smaller C-terminal domain contains nine selenocysteine and ten cysteine residues. Four isoforms of selenoprotein P are present in rat plasma. They share the same N terminus and amino acid sequence. One isoform is full length and the three others terminate at the positions of the second, third, and seventh selenocysteine residues. Selenoprotein P turns over rapidly in rat plasma with the consequence that approximately 25% of the amount of whole-body selenium passes through it each day. Evidence supports functions of the protein in selenium homeostasis and oxidant defense. Selenoprotein P knockout mice have very low selenium concentrations in the brain, the testis, and the fetus, with severe pathophysiological consequences in each tissue. In addition, those mice waste moderate amounts of selenium in the urine. Selenoprotein P binds to endothelial cells in the rat, and plasma levels of the protein correlate with prevention of diquat-induced lipid peroxidation and hepatic endothelial cell injury. The mechanisms of these apparent functions remain speculative and much work on the mechanism of selenoprotein P function lies ahead. Measurement of selenoprotein P in human plasma has shown that it is depressed by selenium deficiency and by cirrhosis. Selenium supplementation of selenium-deficient human subjects showed that glutathione peroxidase activity was optimized before selenoprotein P concentration was optimized, indicating that plasma selenoprotein P is the better index of human selenium nutritional status.
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14 MeSH Terms
Selenoprotein P is required for mouse sperm development.
Olson GE, Winfrey VP, Nagdas SK, Hill KE, Burk RF
(2005) Biol Reprod 73: 201-11
MeSH Terms: Animals, Epididymis, Female, Infertility, Male, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Microscopy, Phase-Contrast, Pregnancy, Proteins, Selenoprotein P, Selenoproteins, Spermatogenesis, Spermatozoa
Show Abstract · Added March 5, 2014
Selenoprotein P (SEPP1), an extracellular glycoprotein of unknown function, is a unique member of the selenoprotein family that, depending on species, contains 10-17 selenocysteines in its primary structure; in contrast, all other family members contain a single selenocysteine residue. The SEPP1-null (Sepp1(-/-)) male but not the female mice are infertile, but the cellular basis of this male phenotype has not been defined. In this study, we demonstrate that mature spermatozoa of Sepp1(-/-) males display a specific set of flagellar structural defects that develop temporally during spermiogenesis and after testicular maturation in the epididymis. The flagellar defects include a development of a truncated mitochondrial sheath, an extrusion of a specific set of axonemal microtubules and outer dense fibers from the principal piece, and ultimately a hairpin-like bend formation at the midpiece-principal piece junction. The sperm defects found in Sepp1(-/-) males appear to be the same as those observed in wild-type (Sepp1(+/+)) males fed a low selenium diet. Supplementation of dietary selenium levels for Sepp1(-/-) males neither reverses the development of sperm defects nor restores fertility. These data demonstrate that SEPP1 is required for development of functional spermatozoa and indicate that it is an essential component of the selenium delivery pathway for developing germ cells.
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16 MeSH Terms
Mass spectrometric determination of selenenylsulfide linkages in rat selenoprotein P.
Ma S, Hill KE, Burk RF, Caprioli RM
(2005) J Mass Spectrom 40: 400-4
MeSH Terms: Amino Acid Sequence, Animals, Chromatography, High Pressure Liquid, Molecular Sequence Data, Proteins, Rats, Selenium, Selenoprotein P, Selenoproteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Structure-Activity Relationship, Sulfides
Show Abstract · Added March 5, 2014
The reversible formation of a selenenylsulfide linkage in mammalian thioredoxin reductase was identified as having a key role in its activity. Identification of selenenylsulfide and/or diselenide linkages is therefore critical to the determination of the structure and function of selenoproteins. A selenopeptide, (298)SGSAITUQCAENLPSLCSUQGLFAEEK(324) (U=selenocysteine), was isolated from a tryptic digest of rat selenoprotein P. Its two cysteine residues and two selenocysteine (Sec) residues were determined to be present in oxidized form by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The selenopeptide was subjected to partial reduction by dithiothreitol with immediate alkylation by iodoacetamide. This process was monitored by MALDI-TOFMS to determine the number of alkylations that had taken place. The partially reduced and alkylated peptides were then analyzed by nano-electrospray ionization tandem mass spectrometry and the results indicated that selenenylsulfide linkages Sec304-Cys314 and Cys306-Sec316 were present. It is concluded that selenoprotein P contains these two selenenylsulfide bonds.
Copyright (c) 2005 John Wiley & Sons, Ltd.
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12 MeSH Terms
Neurological dysfunction occurs in mice with targeted deletion of the selenoprotein P gene.
Hill KE, Zhou J, McMahan WJ, Motley AK, Burk RF
(2004) J Nutr 134: 157-61
MeSH Terms: Animals, Biological Availability, Brain, Creatine Kinase, Diet, Female, Gene Deletion, Male, Mice, Mice, Knockout, Muscle, Skeletal, Nervous System Diseases, Proteins, Selenium, Selenomethionine, Selenoprotein P, Selenoproteins, Sodium Selenite, Weaning
Show Abstract · Added March 5, 2014
Brain function and selenium concentration are well maintained in rodents under conditions of selenium deficiency. Recently, however, targeted deletion of the selenoprotein P gene (Sepp) has been associated with a decrease in brain selenium concentration and with neurological dysfunction. Studies were conducted with Sepp(-/-) and Sepp(+/+) mice to characterize the neurological dysfunction and to correlate it with dietary selenium level. When weanling Sepp(-/-) mice were fed the basal diet (<0.01 mg/kg selenium) supplemented with 0, 0.05 or 0.10 mg selenium/kg, they developed spasticity that progressed and required euthanasia. Supplementing the diet with > or =0.25 mg selenium/kg prevented the neurological dysfunction. To determine whether neurological dysfunction would occur in more mature Sepp(-/-) mice deprived of selenium, Sepp(-/-) mice that had been fed the basal diet supplemented with 1.0 mg selenium/kg for 4 wk were switched to a selenium-deficient diet. Within 3 wk they had developed neurological dysfunction and weight loss. At 3 wk, the 1.0 mg selenium/kg diet was reinstituted. Neurological function stabilized but did not return to normal. Brain selenium concentration did not increase. Weight gain resumed. This study shows that neurological dysfunction occurs when selenium supply to the brain is curtailed and that the dysfunction is not readily reversible. Both the absence of selenoprotein P and a low dietary selenium supply are necessary for the dysfunction to occur, indicating that selenoprotein P and at least one other form of selenium supply the element to the brain.
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19 MeSH Terms
Mass spectrometric identification of N- and O-glycosylation sites of full-length rat selenoprotein P and determination of selenide-sulfide and disulfide linkages in the shortest isoform.
Ma S, Hill KE, Burk RF, Caprioli RM
(2003) Biochemistry 42: 9703-11
MeSH Terms: Amino Acid Sequence, Animals, Binding Sites, Carbohydrate Sequence, Disulfides, Glycosylation, Molecular Sequence Data, Peptide Fragments, Peptide Mapping, Protein Isoforms, Proteins, Rats, Selenium, Selenocysteine, Selenoprotein P, Selenoproteins, Spectrometry, Mass, Electrospray Ionization, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Sulfides
Show Abstract · Added March 5, 2014
Rat selenoprotein P is an extracellular glycoprotein of 366 amino acid residues that is rich in cysteine and selenocysteine. Plasma contains four isoforms that differ principally by length at the C-terminal end. Mass spectrometry was used to identify sites of glycosylation on the full-length protein. Of the potential N-glycosylation sites, three located at residues 64, 155, and 169 were occupied, while the two at residues 351 and 356 were not occupied. Threonine 346 was variably O-glycosylated. Thus, full-length selenoprotein P is both N- and O-glycosylated. The shortest isoform of selenoprotein P, which terminates at residue 244, was analyzed for selenide-sulfide and disulfide linkages. In this isoform, a single selenocysteine and seven cysteines are present. Mass spectrometric analysis indicated that a selenide-sulfide bond exists between Sec40 and Cys43. Two disulfides were also detected as Cys149-Cys167 and Cys153-Cys156. The finding of a selenide-sulfide bond in the shortest isoform is compatible with a redox function of this pair that might be analogous to the selenol-thiol pair near the C terminus of animal thioredoxin reductase. The disulfide formed by Cys153-Cys156 also has some characteristics of a redox active pair.
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19 MeSH Terms