Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer
Laia Coll-SanMartinVerónica DávalosDavid PiñeyroMargalida Rosselló-TortellaAlberto Bueno-CostaFernando SetiénAlberto VillanuevaIsabel GranadaNeus Ruiz-XivillerAnnika KötterMark HelmJun YokotaReika Kawabata‐IwakawaTakashi KohnoManel Esteller
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Abstract:
The alteration of RNA modification patterns is emerging as a common feature of human malignancies. If these changes affect key RNA molecules for mRNA translation, such as transfer RNA, they can have important consequences for cell transformation. TRIT1 is the enzyme responsible for the hypermodification of adenosine 37 in the anticodon region of human tRNAs containing serine and selenocysteine. Herein, we show that TRIT1 undergoes gene amplification-associated overexpression in cancer cell lines and primary samples of small-cell lung cancer. From growth and functional standpoints, the induced depletion of TRIT1 expression in amplified cells reduces their tumorigenic potential and downregulates the selenoprotein transcripts. We observed that TRIT1-amplified cells are sensitive to arsenic trioxide, a compound that regulates selenoproteins, whereas reduction of TRIT1 levels confers loss of sensitivity to the drug. Overall, our results indicate a role for TRIT1 as a small-cell lung cancer-relevant gene that, when undergoing gene amplification-associated activation, can be targeted with the differentiation agent arsenic trioxide.Keywords:
Arsenic Trioxide
Selenocysteine
Selenoprotein
Selenoproteins contain selenium in stoichiometric amounts. Most are synthesized by a process that decodes UGA codons as selenocysteine. Twelve animal selenoproteins have been characterized, and biochemical functions have been described for all but three. Two of these "orphan" selenoproteins are discussed in this paper. Selenoprotein P is an extracellular glycoprotein that contains multiple selenocysteines. It binds heparin and associates with endothelial cells. Two isoforms have been identified. Plasma concentration of selenoprotein P correlates with protection against diquat liver injury, suggesting that the protein protects against oxidant injury. Selenoprotein W is a small intracellular protein that contains one selenocysteine. It binds glutathione and has been suggested to function in oxidant defense. The postulated oxidant defense properties of these selenoproteins are consistent with the facile thiol-redox properties of selenocysteine. It can be predicted that more proteins will be discovered that take advantage of the chemical properties of selenium. BioEssays 21:231–237, 1999. © 1999 John Wiley & Sons, Inc.
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Selenoproteins are unique as they contain selenium in their active site in the form of the 21st amino acid selenocysteine (Sec), which is encoded by an in-frame UGA stop codon. Sec incorporation requires both cis- and trans-acting factors, which are known to be sufficient for Sec incorporation in vitro, albeit with low efficiency. However, the abundance of the naturally occurring selenoprotein that contains 10 Sec residues (SEPP1) suggests that processive and efficient Sec incorporation occurs in vivo. Here, we set out to study native SEPP1 synthesis in vitro to identify factors that regulate processivity and efficiency. Deletion analysis of the long and conserved 3'-UTR has revealed that the incorporation of multiple Sec residues is inherently processive requiring only the SECIS elements but surprisingly responsive to the selenium concentration. We provide evidence that processive Sec incorporation is linked to selenium utilization and that reconstitution of known Sec incorporation factors in a wheat germ lysate does not permit multiple Sec incorporation events, thus suggesting a role for yet unidentified mammalian-specific processes or factors. The relationship between our findings and the channeling theory of translational efficiency is discussed.
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Abstract Selenium is an essential trace element that is required for life, owing to its presence in selenoproteins as the unique amino acid selenocysteine. Selenoproteins are thought to be responsible for most or all of the biological functions of selenium. Incorporation of selenocysteine into proteins requires several specific factors, and it is a tightly regulated process. In addition to the requirement for selenium in selenoprotein biosynthesis, dietary intake of selenium regulates expression or activity of some of the elements of the selenocysteine incorporation machinery. Several transcription factors are implicated in regulating transcription of selenoprotein mRNAs, including members of the NFκB, Nrf2, HIF1, and Sp family. Translation of selenoprotein mRNAs is subject to a hierarchical prioritization that is tissue‐specific and dependent on mechanisms of nonsense‐mediated decay, proper assembling of selenocysteine incorporation factors, as well as selenium concentration. In this article, recent advances in our understanding of the regulation of selenoproteins are discussed.
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Selenoproteins contain selenium in stoichiometric amounts. Most are synthesized by a process that decodes UGA codons as selenocysteine. Twelve animal selenoproteins have been characterized, and biochemical functions have been described for all but three. Two of these "orphan" selenoproteins are discussed in this paper. Selenoprotein P is an extracellular glycoprotein that contains multiple selenocysteines. It binds heparin and associates with endothelial cells. Two isoforms have been identified. Plasma concentration of selenoprotein P correlates with protection against diquat liver injury, suggesting that the protein protects against oxidant injury. Selenoprotein W is a small intracellular protein that contains one selenocysteine. It binds glutathione and has been suggested to function in oxidant defense. The postulated oxidant defense properties of these selenoproteins are consistent with the facile thiol-redox properties of selenocysteine. It can be predicted that more proteins will be discovered that take advantage of the chemical properties of selenium. BioEssays 21:231–237, 1999. © 1999 John Wiley & Sons, Inc.
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Selenium (Se) obtained from dietary sources including cereals, grains and vegetables is an essential micronutrient for normal function of the body. Plants convert Se into selenomethionine and incorporate it into proteins in place of methionine, while higher animals synthesize selenoproteins containing selenocysteine. Excessive Se in the body is methylated stepwise to methylated selenium metabolites from selenide. Both inorganic and organic forms of selenium can be the nutritional sources in human, and they are transformed to selenide and then the amino acid selenocysteine attached to a specific tRNASUPser(sec)/SUP. The selenocysteine (Sec) is incorporated into selenoprotein sequences by the UGA codon. The decoding of UGA as Sec requires specific mechanisms because UGA is normally read as a stop codon: cis -acting sequences in the mRNA (the sele-nocysteine insertion sequence, SECIS, within the 3’untranslated region) and trans -acting factors dedicated to Sec incorporation are required for incorporation of Sec during translation of selenoprotein mRNAs. Approxi-mately 25 selenoproteins have been identified in mammals. Several of these, including glutathione peroxidases, thioredoxin reductases and selenoprotein P, have been purified or cloned, allowing further characterization of their biological function. The antioxidant properties of selenoproteins help prevent cellular damage from free radicals which may contribute to the development of chronic disease such as cancer and heart disease. Other selenoproteins have important roles in regulation of thyroid function and play a role in the immune system. Daily selenium intake was reported to be 42.0±16.9 ㎍/day in Korean adult women. This review focuses on the metabolism and biological functions of selenium, and the nutritional status of selenium in the Korean population.
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Selenocysteine-containing enzymes that have been identified in mammals include the glutathione peroxidase family (GPX1, GPX2, GPX3, and GPX4), one or more iodothyronine deiodinases and two thioredixin reductases. Selenoprotein P, a glycoprotein that contains 10 selenocysteine residues per 43 kDa polypeptide and selenoprotein W, a 10 kDa muscle protein, are unidentified as to function. Levels of all of these selenocysteine-containing proteins in various tissues are affected to different extents by selenium availability. Increased amounts of selenoproteins observed in response to selenium supplementation were shown in several studies to correlate with increases in the corresponding mRNA levels. In general, selenoprotein levels in brain are less sensitive to dietary selenium fluctuation than the corresponding selenoprotein levels in other tissues.
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Background: In animals, the 21st amino acid selenocysteine is incorporated into a restricted subset of proteins by recoding of a UGA stop codon. This recoding requires a distinctive selenocysteine insertion sequence in selenoprotein encoding mRNAs, trans-acting factors and in most cases, adequate dietary intake of selenium. With one exception, selenoproteins contain a single selenocysteine, which is incorporated with low translational efficiency. The exception is selenoprotein P, which in some species is predicted to contain as many as 132 selenocysteines and which is considered to play roles in selenium transport and storage. Objective: This study aimed to develop comparative physiological and evolutionary perspectives on the function(s) of selenoprotein P. Method: The review of the literature on the roles of selenoprotein P in diverse animals. Results: Selenoprotein P contains multiple selenocysteines, making it energetically costly to produce. Furthermore, it is often associated with detrimental effects to the animals that produce it. Possible benefits that outweigh these costs include the general storage and transport of selenium; the transport of both toxic and useful metal ions; and specific functions in reproduction and in the nervous system. Conclusion: A probable reconciliation of the negative effects of producing Selenoprotein P is its benefit in terms of promoting reproductive success.
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Abstract Background: Selenium is an important trace element, and selenocysteine is its predominant form in vivo. The protein containing selenocysteine is selenoprotein, whose special structural features include not only the TGA codon encoding selenocysteine, but also the SECIS element in mRNA and the conservation of selenocysteine flanking region. These special features have led to the development of a series of bioinformatics methods for the prediction and research of selenoprotein genes. There are some studies and reports on the evolution and distribution of selenoprotein genes in prokaryotes and multicellular eukaryotes, but the systematic analysis of single-cell eukaryotes, especially algae, is very limited. Results: In this study, we predicted selenoprotein genes in 137 species of algae by using a program we previously developed. More than 1000 selenoprotein genes were obtained. A database website was built to hold these algae selenoprotein genes (www.selenoprotein.com). These genes belong to 42 selenoprotein families, including three novel selenoprotein gene families. Conclusions: This study reveals the primordial state of the eukaryotic selenoproteome. It is an important clue to explore the significance of selenium for primordial eukaryotes and to build the whole evolutionary spectrum of selenoproteins for all life.
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