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Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA.
Mol Cell Biol. 2001 Jun; 21(11):3840-52.MC

Abstract

Selenocysteine (Sec) tRNA (tRNA([Ser]Sec)) serves as both the site of Sec biosynthesis and the adapter molecule for donation of this amino acid to protein. The consequences on selenoprotein biosynthesis of overexpressing either the wild type or a mutant tRNA([Ser]Sec) lacking the modified base, isopentenyladenosine, in its anticodon loop were examined by introducing multiple copies of the corresponding tRNA([Ser]Sec) genes into the mouse genome. Overexpression of wild-type tRNA([Ser]Sec) did not affect selenoprotein synthesis. In contrast, the levels of numerous selenoproteins decreased in mice expressing isopentenyladenosine-deficient (i(6)A(-)) tRNA([Ser]Sec) in a protein- and tissue-specific manner. Cytosolic glutathione peroxidase and mitochondrial thioredoxin reductase 3 were the most and least affected selenoproteins, while selenoprotein expression was most and least affected in the liver and testes, respectively. The defect in selenoprotein expression occurred at translation, since selenoprotein mRNA levels were largely unaffected. Analysis of the tRNA([Ser]Sec) population showed that expression of i(6)A(-) tRNA([Ser]Sec) altered the distribution of the two major isoforms, whereby the maturation of tRNA([Ser]Sec) by methylation of the nucleoside in the wobble position was repressed. The data suggest that the levels of i(6)A(-) tRNA([Ser]Sec) and wild-type tRNA([Ser]Sec) are regulated independently and that the amount of wild-type tRNA([Ser]Sec) is determined, at least in part, by a feedback mechanism governed by the level of the tRNA([Ser]Sec) population. This study marks the first example of transgenic mice engineered to contain functional tRNA transgenes and suggests that i(6)A(-) tRNA([Ser]Sec) transgenic mice will be useful in assessing the biological roles of selenoproteins.

Authors+Show Affiliations

Section on the Molecular Biology of Selenium, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11340175

Citation

Moustafa, M E., et al. "Selective Inhibition of Selenocysteine tRNA Maturation and Selenoprotein Synthesis in Transgenic Mice Expressing Isopentenyladenosine-deficient Selenocysteine TRNA." Molecular and Cellular Biology, vol. 21, no. 11, 2001, pp. 3840-52.
Moustafa ME, Carlson BA, El-Saadani MA, et al. Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA. Mol Cell Biol. 2001;21(11):3840-52.
Moustafa, M. E., Carlson, B. A., El-Saadani, M. A., Kryukov, G. V., Sun, Q. A., Harney, J. W., Hill, K. E., Combs, G. F., Feigenbaum, L., Mansur, D. B., Burk, R. F., Berry, M. J., Diamond, A. M., Lee, B. J., Gladyshev, V. N., & Hatfield, D. L. (2001). Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA. Molecular and Cellular Biology, 21(11), 3840-52.
Moustafa ME, et al. Selective Inhibition of Selenocysteine tRNA Maturation and Selenoprotein Synthesis in Transgenic Mice Expressing Isopentenyladenosine-deficient Selenocysteine TRNA. Mol Cell Biol. 2001;21(11):3840-52. PubMed PMID: 11340175.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA. AU - Moustafa,M E, AU - Carlson,B A, AU - El-Saadani,M A, AU - Kryukov,G V, AU - Sun,Q A, AU - Harney,J W, AU - Hill,K E, AU - Combs,G F, AU - Feigenbaum,L, AU - Mansur,D B, AU - Burk,R F, AU - Berry,M J, AU - Diamond,A M, AU - Lee,B J, AU - Gladyshev,V N, AU - Hatfield,D L, PY - 2001/5/8/pubmed PY - 2001/6/29/medline PY - 2001/5/8/entrez SP - 3840 EP - 52 JF - Molecular and cellular biology JO - Mol. Cell. Biol. VL - 21 IS - 11 N2 - Selenocysteine (Sec) tRNA (tRNA([Ser]Sec)) serves as both the site of Sec biosynthesis and the adapter molecule for donation of this amino acid to protein. The consequences on selenoprotein biosynthesis of overexpressing either the wild type or a mutant tRNA([Ser]Sec) lacking the modified base, isopentenyladenosine, in its anticodon loop were examined by introducing multiple copies of the corresponding tRNA([Ser]Sec) genes into the mouse genome. Overexpression of wild-type tRNA([Ser]Sec) did not affect selenoprotein synthesis. In contrast, the levels of numerous selenoproteins decreased in mice expressing isopentenyladenosine-deficient (i(6)A(-)) tRNA([Ser]Sec) in a protein- and tissue-specific manner. Cytosolic glutathione peroxidase and mitochondrial thioredoxin reductase 3 were the most and least affected selenoproteins, while selenoprotein expression was most and least affected in the liver and testes, respectively. The defect in selenoprotein expression occurred at translation, since selenoprotein mRNA levels were largely unaffected. Analysis of the tRNA([Ser]Sec) population showed that expression of i(6)A(-) tRNA([Ser]Sec) altered the distribution of the two major isoforms, whereby the maturation of tRNA([Ser]Sec) by methylation of the nucleoside in the wobble position was repressed. The data suggest that the levels of i(6)A(-) tRNA([Ser]Sec) and wild-type tRNA([Ser]Sec) are regulated independently and that the amount of wild-type tRNA([Ser]Sec) is determined, at least in part, by a feedback mechanism governed by the level of the tRNA([Ser]Sec) population. This study marks the first example of transgenic mice engineered to contain functional tRNA transgenes and suggests that i(6)A(-) tRNA([Ser]Sec) transgenic mice will be useful in assessing the biological roles of selenoproteins. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/11340175/Selective_inhibition_of_selenocysteine_tRNA_maturation_and_selenoprotein_synthesis_in_transgenic_mice_expressing_isopentenyladenosine_deficient_selenocysteine_tRNA_ L2 - http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=11340175 DB - PRIME DP - Unbound Medicine ER -