Selenocysteine-containing Proteins Research Articles

Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis.

Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process and is dependent on two tRNASec isodecoders differing by a single 2'-O-ribose methylation called Um34. Here we characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and show decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNASec Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.

Comparing thiol and selenol reactivity towards peroxynitrite by computer simulation

Peroxynitrite is a very reactive species implicated in a variety of pathophysiological cellular processes. Particularly, peroxynitrite-mediated oxidation of cellular thiol-containing compounds such as cysteine residues is a key process which has been extensively studied. Cysteine plays roles in many redox biochemistry pathways. In contrast, selenocysteine, the 21st amino acid, is only present in 25 human proteins. Investigating the molecular basis of selenocysteine's reactivity may provide insights into its unique role in these selenocysteine-containing proteins. The two-electron oxidation of thiols or selenols by peroxynitrite is a process that is carried out by the thiolate/selenate forms and peroxynitrous acid.In this work, we shed light on the molecular basis of the differential reactivity of both species towards peroxynitrite by means of state-of-the-art computer simulations. We performed electronic structure calculations of the reaction in the methanethiolate and methaneselenolate model systems with peroxynitrous acid at different levels of theory using an implicit solvent scheme. In addition, we employed a multi-scale quantum mechanics/molecular mechanics approach for obtaining free energy profiles of these chemical reactions in aqueous solution, which enabled the comparison between the simulations and the available experimental data. Our results suggest that the larger reactivity observed in the selenocysteine case at physiological pH is mainly due to the lower pKa, which affords a larger fraction of the reactive anionic species in these conditions, and in a second place to a slightly enhanced intrinsic reactivity of the selenate form due to its larger nucleophilicity.

The effect of selenium supplements on selenium metabolism, performance and intestinal microbiome in farm animals (review)

Selenium is one of the most important essential elements for immune function and general health of cattle. The role of selenium in maintaining animal health is primarily based on the functions of selenocysteine-containing proteins, many of which have antioxidant activity. Role of selenium in Animal Health is primarily based on the functions of selenocysteine-containing proteins, many of which possess antioxidant activity. Insufficient selenium intake can be accompanied by subclinical diseases, which leads to a decrease in productivity. It was determined that the inclusion of additional sources of selenium has a significant effect on live weight gain, quality characteristics of meat, as well as the intestinal microbiome in cattle and other types of farm animals (pigs, poultry). However, despite the rather high level of knowledge of the selenium role in the implementation of the functional traits in farm animals, there is still no consensus in the scientific community on the optimal dosages and methods of feeding selenium, which reduces the effectiveness of the use of selenium-containing preparations in practical animal husbandry.

Selenium-More than Just a Fortuitous Sulfur Substitute in Redox Biology.

Living organisms use selenium mainly in the form of selenocysteine in the active site of oxidoreductases. Here, selenium's unique chemistry is believed to modulate the reaction mechanism and enhance the catalytic efficiency of specific enzymes in ways not achievable with a sulfur-containing cysteine. However, despite the fact that selenium/sulfur have different physicochemical properties, several selenoproteins have fully functional cysteine-containing homologues and some organisms do not use selenocysteine at all. In this review, selected selenocysteine-containing proteins will be discussed to showcase both situations: (i) selenium as an obligatory element for the protein's physiological function, and (ii) selenium presenting no clear advantage over sulfur (functional proteins with either selenium or sulfur). Selenium's physiological roles in antioxidant defence (to maintain cellular redox status/hinder oxidative stress), hormone metabolism, DNA synthesis, and repair (maintain genetic stability) will be also highlighted, as well as selenium's role in human health. Formate dehydrogenases, hydrogenases, glutathione peroxidases, thioredoxin reductases, and iodothyronine deiodinases will be herein featured.

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation

Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient’s cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.

The selenoprotein P-LRP5/6-WNT3A complex promotes tumorigenesis in sporadic colorectal cancer.

Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique selenocysteine-containing protein, to sporadic colorectal carcinogenesis challenges this paradigm. SELENOP is predominately secreted by the liver but is also expressed in various cells of the small intestine and colon in mice and humans. In this issue of the JCI, Pilat et al. demonstrate that increased SELENOP expression promoted the progression of conventional adenomas to carcinoma. SELENOP functioned as a modulator of canonical WNT signaling activity through interactions with WNT3A and its coreceptor LDL receptor-related protein 5/6 (LRP5/6). Secreted SELENOP formed a concentration gradient along the gut crypt axis, which might amplify WNT signaling activity by binding to LRPL5/6. The mechanism for WNT control via SELENOP may affect colorectal tumorigenesis and provide therapeutic targets for CRC.

59 Supranutritional Selenium Supplementation During Different Trimesters of Pregnancy in Beef Cows Affects Gene Expression of Monocyte Cells

Abstract Selenium (Se) is an essential micronutrient with beneficial effects on performance and immune function. Selenium plays a key role in enzymatic and metabolic pathways, primarily through selenocysteine-containing proteins. Despite increasing knowledge on the role of Se on conceptus development, less is known about its effects on maternal immune responses during gestation. Thus, our goal was to investigate the effects of supranutritional Se-supplementation during different trimesters of pregnancy on gene expression of monocyte blood cells and the underlying biological pathways. To this end, crossbred Angus cows (n = 40) received, except for the control group (CTR), Se-yeast boluses (105 mg of Se/wk) during the first (TR1), second (TR2), or third (TR3) trimester of gestation. Before calving, blood samples were collected from a jugular vein, and the monocytes were isolated and used for total RNA extraction. After quality control of the RNA-Seq data, 13,810 genes were tested for differential expression analysis using a t-test method implemented in the CeTF R-package. We identified 3,904 unique differentially expressed genes (DEGs) across all group comparisons (FDR < 0.05). Differentially expressed selenoprotein-coding genes included SELENOI, SELENOM, SELENON, SELENOP, SELENOT, and SEPSECS. Most of these genes were downregulated in the Se-supplemented groups compared with CTR. However, SELONOP was upregulated in TR1 and TR2 groups, and SELENOM in TR3 compared with CTR. Biological processes over-represented by the DEGs, were retrieved using the WebGestalt software (FDR < 0.05). Immune-related biological processes included positive regulation of the immune system process, immune system development, leukocyte migration, and inflammatory response. Genes underlying these biological processes included ILDR1, IL21R, IL9R, and IL18BP, all of which were upregulated in TR2 compared with CTR. On the other hand, IL1R1, IL6R, and IL1RN genes were downregulated in the Se-supplemented groups. Our results provide evidence that genes underlying immune cell function and Se metabolism were affected by supranutritional Se supplementation.

Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H2O2-dependent biosynthesis and the deiodinase-mediated (in-)activation of thyroid hormones, which is critical for their receptor-mediated mechanism of cellular action. Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus-pituitary-thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H2O2 as cofactor. The latter is generated by the dual oxidase system organized as 'thyroxisome' at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H2O2 and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures.

Abstract PR001: Codon-bias and tRNA modifications as drivers of melanoma metastasis

Abstract Only tumor cells that are able to enhance their stress response pathways, are able to successfully metastasize and colonize distant organs. In yeast, reprogramming of translation through modification of the tRNA anticodon loop in response to stress has been shown to be a central adaptive mechanism of survival. Distinct tRNA modifications increase translational efficiency of certain codons. These modifications are upregulated and are essential for survival under a range of stressors, including oxidative stress. The adaptive proteome is therefore encoded by specific transcripts with a distinct codon bias and regulated by these tRNA modifications. We have identified several stress-induced tRNA anticodon loop modifications in metastasizing melanoma cells that drive codon-biased translation of the adaptive pro-metastatic proteome. One of these modifications specifically regulates stress-induced translation of selenocysteine-containing proteins. Selenoproteins are central to stress resistance including oxidative and proteotoxic stress. We have identified and characterized the methyltransferase that regulates this modification and enables translation of the metastatic selenoproteome. More broadly, by combining biochemical approaches with in vivo models of melanoma metastasis, we have now identified several other enzymes responsible for multiple tRNA anticodon modifications as novel and targetable drivers of metastatic disease. Our work aims to establish how tRNA anticodon modifications and a distinct codon bias reprogram the metastatic proteome as a therapeutically targetable stress response mechanism. Citation Format: Elena Piskounova. Codon-bias and tRNA modifications as drivers of melanoma metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR001.

The semisynthesis of nucleolar human selenoprotein H.

The human selenoprotein H is the only selenocysteine-containing protein that is located in the cell's nucleolus. In vivo studies have suggested that it plays some role in DNA binding, consumption of reactive oxygen species, and may serve as a safeguard against cancers. However, the protein has never been isolated and, as a result, not yet fully characterized. Here, we used a semi-synthetic approach to obtain the full selenoprotein H with a S43T mutation. Using biolayer interferometry, we also show that the Cys-containing mutant of selenoprotein H is capable of binding DNA with sub-micromolar affinity. Employing state-of-the-art expressed protein ligation (EPL), our devised semi-synthetic approach can be utilized for the production of numerous, hard-to-obtain proteins of biological and therapeutic relevance.

Role of SELENBP1 and SELENOF in prostate cancer bioenergetics

The contribution of selenium and selenoproteins in prostate cancer etiology remains elusive, potentially due to insufficient information regarding the biochemical pathways in which they are involved. There are twenty-five human selenocysteine-containing proteins or selenoproteins as well as a smaller class of selenium-containing proteins that do not include selenocysteine, and their cancer-associated aberrations, both genetic and functional, have evoked special interest, although their contribution to the metabolic reprogramming of prostate cancers remains has not been extensively studied. While benign prostate tissue exhibits a glycolytic phenotype, neoplastic events restore the truncated tricarboxylic acid cycle and enhance oxidative phosphorylation. Two selenium-containing proteins, selenium binding protein 1 and selenoprotein F, affect prostate cancer phenotypes by modulating tumor cell metabolic profiles with significant effects on mitochondrial biology, including oxidative phosphorylation and ATP synthesis. One of the pathways affected by both proteins is the activation of adenosine monophosphate kinase and its downstream signaling with concomitant induction of glycolysis. This review focuses on highlighting the role of these two proteins in modulating the bioenergetic profile of prostate cancer and in maintaining the metabolic plasticity of these cells rendering growth advantage and possible therapeutic resistance.

GPX4: old lessons, new features.

GPX4 is a selenocysteine-containing protein that plays an essential role in repairing peroxidised phospholipids. Its role in organismal homeostasis has been known for decades, and it has been reported to play a pivotal role in cell survival and mammalian embryonic development. In recent years, GPX4 has been associated with a cell death modality dubbed ferroptosis. The framing of this molecular pathway of cell death was essential for understanding the conditions that determine GPX4 dependency and ultimately to the process of lipid peroxidation. Since its discovery, ferroptosis has been gaining momentum as a promising target for yet-incurable diseases, including cancer and neurodegeneration. Given the current interest, in the present review, we provide newcomers in the field with an overview of the biology of GPX4 and cover some of its most recent discoveries.

Genomic Characterization of Campylobacter jejuni Adapted to the Guinea Pig (Cavia porcellus) Host

Campylobacter jejuni is the leading bacterial cause of gastroenteritis worldwide with excessive incidence in low-and middle-income countries (LMIC). During a survey for C. jejuni from putative animal hosts in a town in the Peruvian Amazon, we were able to isolate and whole genome sequence two C. jejuni strains from domesticated guinea pigs (Cavia porcellus). The C. jejuni isolated from guinea pigs had a novel multilocus sequence type that shared some alleles with other C. jejuni collected from guinea pigs. Average nucleotide identity and phylogenetic analysis with a collection of C. jejuni subsp. jejuni and C. jejuni subsp. doylei suggest that the guinea pig isolates are distinct. Genomic comparisons demonstrated gene gain and loss that could be associated with guinea pig host specialization related to guinea pig diet, anatomy, and physiology including the deletion of genes involved with selenium metabolism, including genes encoding the selenocysteine insertion machinery and selenocysteine-containing proteins.

The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models.

MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.

Selenocysteine insertion sequence binding protein 2 (Sbp2) in the sex-specific regulation of selenoprotein gene expression in mouse pancreatic islets

Selenoproteins are a group of selenocysteine-containing proteins with major roles in cellular antioxidant defense and thyroid hormone metabolism. Selenoprotein expression is determined by hierarchical mechanisms that result in tissue-specific levels. Current data inadequately explain the abundance of various selenoproteins under normal and pathological conditions, including in pancreatic β-cells. Selenocysteine insertion sequence binding protein 2 (SBP2) is a critical protein in selenoprotein translation that also plays an essential role in stabilizing selenoprotein transcripts by antagonizing nonsense-mediated decay (NMD). Importantly, dysfunctional SBP2 is associated with endocrine disorders in humans. Here we describe the impact of induced Sbp2 deficiency in pancreatic β-cells on selenoprotein transcript profiles in the pancreatic islets of C57BL/6J mice. Sex differences were noted in control mice, in which female islets showed 5 selenoproteins decreased and one increased versus male islets. Induced Sbp2 deficiency in pancreatic β-cells altered expression of only 3 selenoprotein transcripts in male islets, whereas 14 transcripts were reduced in female islets. In all cases, decreased transcription was observed in genes known to be regulated by NMD. The differential impact of Sbp2 deletion on selenoprotein transcription between sexes suggests sex-specific hierarchical mechanisms of selenoprotein expression that may influence islet biology and consequentially metabolic disease risk.

Control of Selenoprotein F Translation in Prostate Cancer

Abstract Objectives Selenoprotein F (SELENOF) is a selenocysteine-containing protein whose levels are responsive to selenium availability and are often lower in prostate cancer (PCa) compared to benign regions. Lowering SELENOF levels in cultured, non-transformed prostate cells results in these cells gaining a transformed phenotype, indicating that SELENOF may function as a tumor suppressor. The reasons for the loss of SELENOF in PCa remain unknown. SELENOF translation requires a selenocysteine insertion sequence (SECIS), a stem-loop structure within the 3’– untranslated region (UTR) of the SELENOF mRNA. The objective of this study is to determine if SECIS-mediated UGA recoding is impeded in PCa, resulting in lower SELENOF protein levels. Methods In order to establish a cell model for the decrease in SELENOF levels, SELENOF levels were determined by western blot analysis of protein from PC3 PCa cells and RWPE-1 immortalized but not tumorigenic prostate cells. SELENOF mRNA levels in each of these cell lines was subsequently determined by RT-qPCR. In order to determine the efficiency of UGA readthrough in PC3 and RWPE-1 cells, reporter constructs were generated in which an in-frame UGA was introduced into the open reading frame of firefly luciferase by in-vitro mutagenesis and the constructs included portions of the SELENOF 3’-UTR required for UGA recoding. Results SELENOF levels were 18 times lower in PC3 cells compared to the RWPE-1 cells, while mRNA levels were similar between the two. Using the generated reporter constructs, differences in UGA recoding efficiency in PC3 and RWPE-1 cells were apparent, as were unexpected contributions of portions of the 3’UTR sequences to UGA readthrough efficiency. Conclusions Differing levels of SELENOF seen in prostate tissues were recapitulated in a cell culture model, with there being significantly less protein in PC3 cells compared to RWPE-1 cells, without a comparable difference in mRNA. Changes in SELENOF levels due to altered regulation of UGA recoding may be a significant event in PCa progression. Funding Sources This work was supported by the University of Illinois at Chicago Liberal Arts and Sciences Undergraduate Research Initiative (LASURI) to SK and Department of Defense Prostate Cancer Research Program to AMD.

Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding.

SummaryThe UGA codon signals protein translation termination, but it can also be translated into selenocysteine (Sec, U) to produce selenocysteine-containing proteins (selenoproteins) by dedicated machinery. As Sec incorporation can fail, Sec-containing longer and Sec-lacking shorter proteins co-exist. Cul2-type ubiquitin ligases were recently shown to destabilize such truncated proteins; however, which ubiquitin ligase targets truncated proteins for degradation remained unclear. We report that the Cul5-type ubiquitin ligase KLHDC1 targets truncated SELENOS, a selenoprotein, for proteasomal degradation. SELENOS is involved in endoplasmic reticulum (ER)-associated degradation, which is linked to reactive oxygen species (ROS) production, and the knockdown of KLHDC1 in U2OS cells decreased ER stress-induced cell death. Knockdown of SELENOS increased the cell population with lower ROS levels. Our findings reveal that, in addition to Cul2-type ubiquitin ligases, KLHDC1 is involved in the elimination of truncated oxidoreductase-inactive SELENOS, which would be crucial for maintaining ROS levels and preventing cancer development.

Selenium in Hyperthyroidism

Introduction: Thyroid gland has the highest selenium content compare with other endocrine organs. Enzyme that catalyzing thyroid hormone activation, iodothyronine deiodinases, were identified as selenocysteine-containing proteins. Selenium levels in soil and rice consumed in Indonesia were lower than in several other countries, which can increase the risk of selenium deficiency.Methods: This is an article review of the current literatures published up to November 2018 about the role of selenium in hyperthyroid.Result: Several studies have shown that selenium supplementation can be beneficial in patients with Graves disease and autoimmune thyroiditis. Selenium has an important immunomodulatory effect, but the effects of selenium supplementation in hyperthyroid has not been conclude. Data regarding selenium intake, prevalence of deficiency, and the relationship between selenium and thyroid disease in Indonesia are limited. Various studies of selenium supplementation in thyroid disease provide controversial results, so there are no guidelines that include selenium as standard therapy hyperthyroid. Selenium supplementation can enhance the restoration of biochemical euthyroidism in Graves disease and was associated with a significant decrease in the levels of thyroid peroxidase antibodies in autoimmune thyroiditis.Conclusions: Micronutrients that play a role in thyroid hormone synthesis and maintain thyroid function in addition to selenium are iodine, iron, zinc, and vitamin A. By correcting the deficit of selenium, and meeting other micronutrient requirements may provide health benefits in patient with hyperthyroid.

Chemical Biology Approaches to Interrogate the Selenoproteome.

Selenoproteins are the family of proteins that contain the amino acid selenocysteine. Many selenoproteins, including glutathione peroxidases and thioredoxin reductases, play a role in maintaining cellular redox homeostasis. There are a number of examples of homologues of selenoproteins that utilize cysteine residues, raising the question of why selenocysteines are utilized. One hypothesis is that incorporation of selenocysteine protects against irreversible overoxidation, typical of cysteine-containing homologues under high oxidative stress. Studies of selenocysteine function are hampered by challenges both in detection and in recombinant expression of selenoproteins. In fact, about half of the 25 known human selenoproteins remain uncharacterized. Historically, selenoproteins were first detected via labeling with radioactive 75Se or by use of inductively coupled plasma-mass spectrometry to monitor nonradioactive selenium. More recently, tandem mass-spectrometry techniques have been developed to detect selenocysteine-containing peptides. For example, the isotopic distribution of selenium has been used as a unique signature to identify selenium-containing peptides from unenriched proteome samples. Additionally, selenocysteine-containing proteins and peptides were selectively enriched using thiol-reactive electrophiles by exploiting the increased reactivity of selenols relative to thiols, especially under low pH conditions. Importantly, the reactivity-based enrichment of selenoproteins can differentiate between oxidized and reduced selenoproteins, providing insight into the activity state. These mass spectrometry-based selenoprotein detection approaches have enabled (1) production of selenoproteome expression atlases, (2) identification of aging-associated changes in selenoprotein expression, (3) characterization of selenocysteine reactivity across the selenoprotein family, and (4) interrogation of selenoprotein targets of small-molecule drugs. Further investigations of selenoprotein function would benefit from recombinant expression of selenoproteins. However, the endogenous mechanism of selenoprotein production makes recombinant expression challenging. Primarily, selenocysteine is biosynthesized on its own tRNA, is dependent on multiple enzymatic steps, and is highly sensitive to selenium concentrations. Furthermore, selenocysteine is encoded by the stop codon UGA, and suppression of that stop codon requires a selenocysteine insertion sequence element in the selenoprotein mRNA. In order to circumvent the low efficiency of the endogenous machinery, selenoproteins have been produced in vitro through native chemical ligation and expressed protein ligation. Attempts have also been made to engineer the endogenous machinery for increased efficiency, including recoding the selenocysteine codon, and engineering the tRNA and the selenocysteine insertion sequence element. Alternatively, genetic code expansion can be used to generate selenoproteins. This approach allows for selenoprotein production directly within its native cellular environment, while bypassing the endogenous selenocysteine incorporation machinery. Furthermore, by incorporating a caged selenocysteine by genetic code expansion, selenoprotein activity can be spatially and temporally controlled. Genetic code expansion has allowed for the expression and uncaging of human selenoproteins in E. coli and more recently in mammalian cells. Together, advances in selenoprotein detection and expression should enable a better understanding of selenoprotein function and provide insight into the necessity for selenocysteine production.

Selenoproteins of the Human Prostate: Unusual Properties and Role in Cancer Etiology.

The prostate is an important organ for the maintenance of sperm health with prostate cancer being a common disease for which there is a critical need to distinguish indolent from aggressive disease. Several selenium-containing proteins have been implicated in prostate cancer risk or outcome due to either enzyme function, the reduced levels of these proteins being associated with cancer recurrence after prostatectomy or their corresponding genes containing single-nucleotide polymorphisms associated with increased risk. Moreover, experimental data obtained from the manipulation of either cultured cells or animal models have indicated that some of these proteins are contributing mechanistically to prostate cancer incidence or progression. Among these are selenocysteine-containing proteins selenoprotein P (SELENOP), glutathione peroxidase (GPX1), and selenoprotein 15 (SELENOF); and the selenium-associated protein selenium-binding protein 1 (SBP1). Genotyping of some of the genes for these proteins has identified functional single-nucleotide polymorphisms that are associated with prostate cancer risk and the direct quantification of these proteins in human prostate tissues has not only revealed associations to clinical outcomes but have also identified unique properties that are different from what is observed in other tissue types. The location of GPX1 in the nucleus and SELENOF in the plasma membrane of prostate epithelial cells indicates that these proteins may have functions in normal prostate tissue that are distinct from that of the other tissue types.