Absolute Gene Expression Patterns of Thioredoxin and Glutaredoxin Redox Systems in Mouse

Abstract

This work provides the first absolute expression patterns of genes coding for all known components of both thioredoxin (Trx) and glutaredoxin (Grx) systems in mouse: Trx1, Trx2, Grx1, Grx2, TrxR1, TrxR2, thioredoxin/glutathione reductase, and glutathione reductase. We devised a novel assay that, combining the advantages of multiplex and real-time PCR, streamlines the quantitation of the actual mRNA copy numbers in whole-animal experiments. Quantitations reported establish differences among adult organs and embryonic stages, compare mRNA decay rates, explore the significance of alternative mRNA isoforms derived from TrxR1 and Grx2 genes, and examine the time-course expression upon superoxide stress promoted by paraquat. Collectively, these quantitations show: i) unique expression profiles for each transcript and mouse organ examined, yet with some general trends like the higher amounts of mRNA species coding for thioredoxins than those coding for the reductases that control their redox states and activities; ii) continuous expression during embryogenesis with outstanding up-regulations of Trx1 and TrxR1 mRNAs in specific temporal sequences; iii) drastic differences in mRNA stability, liver decay rates range from 2.8 h (thioredoxin/glutathione reductase) to ≥ 35 h (Trx1 and Trx2), and directly correlate with mRNA steady-state values; iv) testis-specific differences in the amounts (relative to total isoforms) of transcripts yielding the mitochondrial Grx2a and 67-kDa TrxR1 variants; and v) coordinated up-regulation of TrxR1 and glutathione reductase mRNAs in response to superoxide stress in an organ-specific manner. Further insights into in vivo roles of these redox systems should be gained from more focused studies of the mechanisms underlying the vast differences reported here at the transcript level. This work provides the first absolute expression patterns of genes coding for all known components of both thioredoxin (Trx) and glutaredoxin (Grx) systems in mouse: Trx1, Trx2, Grx1, Grx2, TrxR1, TrxR2, thioredoxin/glutathione reductase, and glutathione reductase. We devised a novel assay that, combining the advantages of multiplex and real-time PCR, streamlines the quantitation of the actual mRNA copy numbers in whole-animal experiments. Quantitations reported establish differences among adult organs and embryonic stages, compare mRNA decay rates, explore the significance of alternative mRNA isoforms derived from TrxR1 and Grx2 genes, and examine the time-course expression upon superoxide stress promoted by paraquat. Collectively, these quantitations show: i) unique expression profiles for each transcript and mouse organ examined, yet with some general trends like the higher amounts of mRNA species coding for thioredoxins than those coding for the reductases that control their redox states and activities; ii) continuous expression during embryogenesis with outstanding up-regulations of Trx1 and TrxR1 mRNAs in specific temporal sequences; iii) drastic differences in mRNA stability, liver decay rates range from 2.8 h (thioredoxin/glutathione reductase) to ≥ 35 h (Trx1 and Trx2), and directly correlate with mRNA steady-state values; iv) testis-specific differences in the amounts (relative to total isoforms) of transcripts yielding the mitochondrial Grx2a and 67-kDa TrxR1 variants; and v) coordinated up-regulation of TrxR1 and glutathione reductase mRNAs in response to superoxide stress in an organ-specific manner. Further insights into in vivo roles of these redox systems should be gained from more focused studies of the mechanisms underlying the vast differences reported here at the transcript level. Thioredoxin (Trx) 1The abbreviations used are: Trx, thioredoxin; Grx, glutaredoxin; TrxR, thioredoxin reductase; GR, glutathione reductase; GSH, glutathione; TGR, thioredoxin/glutathione reductase; PQ, paraquat; AmD, actinomycin D; MPCR, multiplex polymerase chain reaction; E, embryonic day; ROS, reactive oxygen species; UTR, untranslated region; HEX, 4,7,2′,4′,5′,7′-hexachloro-6-carboxyfluorescein. and glutaredoxin (Grx) are ubiquitous proteins with redox-active cysteines. They were discovered as independent hydrogen donors for the essential enzyme ribonucleotide reductase. Subsequently, they were shown to be general thiol-disulfide oxidoreductases. Trx and Grx differ in their specific reductive pathways, although ultimately reducing equivalents come from NADPH. Thus, the Trx system is composed of NADPH, thioredoxin reductase (TrxR), and Trx; the Grx system of NADPH, glutathione reductase (GR), glutathione (GSH), and Grx (1Holmgren A. J. Biol. Chem. 1989; 264: 13963-13966Abstract Full Text PDF PubMed Google Scholar). The properties and multiple physiological functions assigned to these systems have been reviewed, particularly in relation to redox control of cell functions and protection against oxidative damage (2Arnér E.S. Holmgren A. Eur. J. Biochem. 2000; 267: 6102-6109Crossref PubMed Scopus (2001) Google Scholar, 3Holmgren A. Antioxid Redox Signal. 2000; 2: 811-820Crossref PubMed Scopus (413) Google Scholar). Two Trxs have been described in mammals, one predominantly cytosolic (Trx1) (4Tagaya Y. Maeda Y. Mitsui A. Kondo N. Matsui H. Hamuro J. Brown N. Arai K. Yokota T. Wakasugi H. Yodoi J. EMBO J. 1989; 8: 757-764Crossref PubMed Scopus (516) Google Scholar) and one mitochondrial (Trx2) (5Spyrou G. Enmark E. Miranda-Vizuete A. Gustafsson J. J. Biol. Chem. 1997; 272: 2936-2941Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar). The cytosolic Trx1 performs many biological actions in defense against oxidative stress, regulation of gene expression, and control of growth and apoptosis, and it has also been implicated in many pathological situations including cancer (6Powis G. Montfort W.R. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 261-295Crossref PubMed Scopus (331) Google Scholar). Trx1 and Trx2 are composed of only a thioredoxin domain (6Powis G. Montfort W.R. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 261-295Crossref PubMed Scopus (331) Google Scholar). A second group of proteins with additional domains, like the spermatid-specific thioredoxins Sptrx1 and Sptrx2, have been also identified within the thioredoxin family (7Sadek C.M. Damdimopoulos A.E. Pelto-Huikko M. Gustafsson J.A. Spyrou G. Miranda-Vizuete A. Genes Cells. 2001; 6: 1077-1090Crossref PubMed Scopus (76) Google Scholar). Grxs are regarded as reductants of disulfides via GSH controlling also the levels of GSH-mixed disulfides, particularly under conditions of oxidative stress (3Holmgren A. Antioxid Redox Signal. 2000; 2: 811-820Crossref PubMed Scopus (413) Google Scholar). Like Trxs, Grxs are being implicated in a growing list of pivotal functions such as cellular differentiation (8Takashima Y. Hirota K. Nakamura H. Nakamura T. Akiyama K. Cheng F.S. Maeda M. Yodoi J. Immunol. Lett. 1999; 68: 397-401Crossref PubMed Scopus (45) Google Scholar), apoptosis (9Chrestensen C.A. Starke D.W. Mieyal J.J. J. Biol. Chem. 2000; 275: 26556-26565Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar), and regulation of transcription factor binding activity (10Bandyopadhyay S. Starke D.W. Mieyal J.J. Gronostajski R.M. J. Biol. Chem. 1998; 273: 392-397Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Nowadays two different isoenzymes of mammalian Grxs have been described, the classical cytosolic enzyme (Grx1) and a novel mitochondrial protein (Grx2) with alternative splice variants (11Lundberg M. Johansson C. Chandra J. Enoksson M. Jacobsson G. Ljung J. Johansson M. Holmgren A. J. Biol. Chem. 2001; 276: 26269-26275Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 12Gladyshev V.N. Liu A. Novoselov S.V. Krysan K. Sun Q.A. Kryukov V.M. Kryukov J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). A gene for has been described in mammalian shown to a mitochondrial it to be to T. Biochem. 1997; PubMed Scopus Google Scholar, Biochem. 2000; PubMed Scopus Google Scholar). GSH is in the for of the cellular GSH H. Biol. 1999; PubMed Scopus Google Scholar). and GSH with Grx2 a in from in the chain (11Lundberg M. Johansson C. Chandra J. Enoksson M. Jacobsson G. Ljung J. Johansson M. Holmgren A. J. Biol. Chem. 2001; 276: 26269-26275Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar). are to and have a a in the E.S. Ljung J. Holmgren A. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). only protein such as that in Trx also a of and and (3Holmgren A. Antioxid Redox Signal. 2000; 2: 811-820Crossref PubMed Scopus (413) Google Scholar). isoenzymes of mammalian have been described Q.A. Y. V.N. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (263) Google Scholar). TrxR1 and is as the cytosolic enzyme S. G. Lett. PubMed Scopus Google Scholar, H. T. M. 2000; PubMed Scopus Google Scholar). TrxR1 a 67-kDa with an additional has been identified Q.A. V.M. V.N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). and is to as the mitochondrial H. T. M. 2000; PubMed Scopus Google Scholar, A. Damdimopoulos A.E. Spyrou G. 1999; PubMed Scopus Google Scholar, G. Lett. 1999; PubMed Scopus Google Scholar). with Trx2 a mitochondrial Trx different from the one in the The described as a novel of Q.A. Y. V.N. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (263) Google Scholar). thioredoxin/glutathione reductase for thioredoxin and glutathione reductase. components of both Trx and Grx This is by a of and Grx Q.A. S. V.N. S. A. 2001; PubMed Scopus Google Scholar). This work the of the expression of genes coding for proteins of mouse Trx and Grx of mRNA levels is in protein in mammalian the of the in vivo of mRNA levels should for the roles of the Trxs and and reductases TGR, and known in transcription by is the for and quantitation of the of multiplex and real-time for quantitation of the of mRNA We to the organ alternative and stress conditions the absolute expression patterns of were for these and of of were from a were into of were by with at a of in mRNA decay were with of actinomycin in with as at the in expression levels were in were by The organs were and in were to the by the The by the of were by from each and and of and of were as C. PubMed Scopus Google Scholar). were from those of total from and of by of of genes were from for were with the and were to have and Two of were for Grx2 and TrxR1 within of Grx2 gene all known of alternative and only those transcripts with the mitochondrial V.N. Liu A. Novoselov S.V. Krysan K. Sun Q.A. Kryukov V.M. Kryukov J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). within and of TrxR1 gene all of alternative by and to transcripts the 67-kDa of mouse TrxR1 Q.A. V.M. V.N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, 2001; 2: PubMed Scopus Google Scholar). in specific of the and of used for absolute quantitation of mRNA were by of both multiplex and real-time for Grx2a and mRNA The an with a in a of numbers were to those for Grx2 and and TrxR1 and that were to 12Gladyshev V.N. Liu A. Novoselov S.V. Krysan K. Sun Q.A. Kryukov V.M. Kryukov J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google and 2001; 2: PubMed Scopus Google Scholar, were liver those for and and that for Grx2a that were and were for in a conditions were as C. PubMed Scopus Google Scholar). were in were transcripts in the range of to of total with absolute with an in the range of to The of from the of the used to the copy of each transcript in the the copy of the transcript in each and the the copy of Grx2a and mRNA of the were as described C. J. J. PubMed Scopus Google Scholar). were at conditions were as C. J. J. PubMed Scopus Google Scholar) to that the were in the and the in the of the of were were in were as C. J. J. PubMed Scopus Google Scholar), with the that the of the transcripts transcripts Grx2a and were by in all used to the the by of each and the of the in the by the in each by those by the liver from the were from to and the copy of the in the these were by real-time for of different conditions were in of mRNA and a in all transcripts and one are in a are used and are with a expression of the to the is and of mRNA levels among different are C. J. J. PubMed Scopus Google Scholar, G. Holmgren A. J. C. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). in gene expression be by the are the have the the of quantitation in and have the quantitation of the copy of transcripts by of real-time C. PubMed Scopus Google Scholar). real-time of a of transcripts in a of is and first devised a novel that the advantages of both multiplex and real-time the mouse genes of the Trx and Grx a of were were for all transcripts in all by MPCR, and absolute were by by real-time the actual mRNA of one gene in all and those of all genes in one and that the of mRNA from is to that by real-time of mRNA copy from were in of total from mouse and by of both multiplex and real-time The numbers of mRNA of total were by real-time and from and as the and the transcript used as an the mRNA in of real-time are with some of the derived from those Trx1, Grx1, TrxR2, as total in a of Trx and Grx first to the steady-state amounts of transcripts at the organ the organs examined, the Trx1 mRNA amounts were in and of and the in by The Trx2 mRNA expression correlate with that of Trx2 mRNA with expression in levels were also in and of and in the of Trx and Grx2 mRNAs were and vast differences in the Thus, mRNA in with the in and with the levels in mouse organs of Grx2 mRNA in with and of and the of organs of is the first that the organ of mouse Trx and Grx mRNAs has been it a Grx2 mRNA in mouse the of from organ V.N. Liu A. Novoselov S.V. Krysan K. Sun Q.A. Kryukov V.M. Kryukov J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of expression patterns of TrxR1, TrxR2, TGR, and mRNAs are in TrxR1 transcript more in liver and than in the of organs of the the mRNA levels in by levels in and and levels in and TrxR1 and different organ expression patterns that were also from those by both Trx the here are in with of mouse TrxR1 and genes Q.A. Y. V.N. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (263) Google Scholar, H. T. M. 2000; PubMed Scopus Google Scholar, A. Damdimopoulos A.E. Spyrou G. 1999; PubMed Scopus Google Scholar). of mouse mRNA higher expression levels in liver than in H. T. M. 2000; PubMed Scopus Google Scholar). the a higher a factor of of mRNA in than in This and be at in by the of the gene as in organ mRNA C. 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Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The levels of mRNA were with a second of within the TrxR1 gene the and the mRNA in all examined, at a that in from to of mRNA that the mRNA is in mouse The in of total TrxR1 This in the of mouse of expression patterns during embryonic J. and Scholar). the of transcripts here is from mouse at different are with of being for by S. J. Biol. Chem. Google Scholar). mitochondrial of are in of A of in Trx1 mRNA as as in the mouse the of Trx1 mRNA to the steady-state in adult to Trx1 mRNA were in expression of Trx2, Grx1, and Grx2 during mouse The Grx2a mRNA with the mitochondrial an of at in Grx2a mRNA of total Grx2 with in of to the in adult transcript coding for TrxR1 with a of at to adult levels were for transcripts coding for the for the of mRNA at in adult the in mouse it at of at the of total TrxR1 is higher than in adult mRNA steady-state of mRNA is both of and of it that the of a mRNA is an to be to The of mRNA the transcription for of the of The in liver from 2.8 h to 35 h (Trx1 transcripts Trx1 and Trx2 to than those the TrxR1 and mRNAs that the mitochondrial Trx system and more than those the system in the (Trx1 and mRNAs that both Trxs were more than those both the decay of the mRNA that the unique the decay rates of transcripts for both We to a the decay rates of mRNAs and their steady-state amounts by the these in mouse A and mitochondrial isoforms were for for organ-specific in mRNA stability, mouse organs were in and than in the decay rates of transcripts be in these The were the TrxR1 and these in and and and were to those in liver and 2.8 in mRNA levels that of that mouse organ at the and used higher than and than h be used the of The decay of Grx2a mRNA the mitochondrial than that for the of Grx2 variants h in mouse The decay of mRNA be of copy in mouse organs than the of transcripts under an were with superoxide at the of the Toxicol. Pharmacol. PubMed Scopus Google Scholar). in and were coding for the of C. PubMed Scopus Google and is the organ of the transcript levels of both TrxR1 and genes of the that of TrxR1 mRNA in have more and a higher than that for in of absolute the at h of an of TrxR1 mRNA mRNA their steady-state up-regulation also in mouse the in both TrxR1 and mRNA levels were than those in to is shown in of mRNA levels at the conditions in response in for of the mRNA species This of has to be in of organ up-regulation in both mouse organs for mRNA Trx and Grx are redox that in the redox control of a of biological in of a novel assay that multiplex and real-time PCR, the first of the actual mRNA levels of mouse Trxs and Grxs and those of TGR, and as of the Trx and Grx The absolute quantitation of the steady-state levels of transcript organs in a unique expression for each gene and organ patterns of expression the for different proteins to to the specific functions of the different mouse a outstanding are as i) Trx1 and Trx2 mRNAs are more factor of than TrxR1 and This the for higher levels of Trxs than for the reductases that in control the redox and activity of these ii) among the mouse organs is for mRNA species of the Trx Trx2, TrxR1, and than for mRNA species of the Grx Grx2, and This the of the Trx system in and specific functions than the Grx iii) Trx and Grx have levels of expression in as by the of Trx1, Trx2, and TrxR1 and of and This a to iv) the is in it in amounts as as of total This is with the that as the reducing system for the of thioredoxin proteins with testis-specific expression (7Sadek C.M. Damdimopoulos A.E. Pelto-Huikko M. Gustafsson J.A. Spyrou G. Miranda-Vizuete A. Genes Cells. 2001; 6: 1077-1090Crossref PubMed Scopus (76) Google Scholar). the of mRNA in mouse organ the of some additional for all these We also that transcripts for proteins of mouse Trx and Grx are during that these systems essential functions for Trx1 and TrxR1 transcripts up-regulation in specific temporal The outstanding of Trx1 mRNA at of is with the that Trx1 M. M. H. K. T. Yodoi J. Biol. PubMed Scopus Google Scholar). This up-regulation the of Trx1 in cell (6Powis G. Montfort W.R. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 261-295Crossref PubMed Scopus (331) Google Scholar), the cell at of and the that oxidative is yet in S. J. Biol. Chem. Google Scholar). The from to in the mouse to the up-regulation for TrxR1 mRNA in the that TrxR1 mRNA in response to of the first is a for protein species that differ in their and for expression of a protein in a M. in and Scholar). A Q.A. V.M. V.N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) a within at in from the of alternative first We here that the transcript the 67-kDa of TrxR1 identified in mouse liver Q.A. V.M. V.N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) is in all at the expression in and in embryogenesis the of a properties should be the that Grx2 transcripts are in the Grx2a mRNA with the mitochondrial is to some the Grx2 alternative splice in expression of proteins and in biological they be predominantly (11Lundberg M. Johansson C. Chandra J. Enoksson M. Jacobsson G. Ljung J. Johansson M. Holmgren A. J. Biol. Chem. 2001; 276: 26269-26275Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 12Gladyshev V.N. Liu A. Novoselov S.V. Krysan K. Sun Q.A. Kryukov V.M. Kryukov J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The of mRNAs is an of the gene expression Y. Liu Brown S. A. PubMed Scopus Google Scholar). mammalian mRNA have come from with the have quantitations in studies are J. Rev. PubMed Google Scholar). have the decay rates in of the mRNAs the group of proteins of the Trx and Grx We drastic differences of more than among the of these that their decay rates are directly to their steady-state at to mouse The mRNAs both Trxs are as by the transcript the novel is with a of 2.8 The decay of TrxR1 mRNA is only is with those of the of transcripts in is the range of mRNA decay that to the regulation of gene expression in higher mRNAs a for genes that are at mRNAs that for proteins in response to to have J. G. 2001; PubMed Scopus Google Scholar). Like and mRNA is a of specific controlling the of mRNAs are in the of many mammalian like the A. S. A. J. PubMed Scopus Google Scholar). The of the mRNA coding for TrxR1 mRNA levels in G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). of the of the mouse H. T. 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Thus, control of mouse TrxR1 mRNA levels be from in both and of the that the TrxR1 mRNA in reported here the of the organ TrxR1 mRNA in and liver to the by PQ, in the mRNA a and organ as higher up-regulation in to than in liver to and to The mRNA of of the to the conditions to in a as the mRNA of TrxR1 of the Trx The of both TrxR1 and to to the of a coordinated cellular and a The in that TrxR1 and a first of defense against in should a into the in vivo that TrxR1 and mRNA levels in mouse and physiological TrxR1 and mRNAs were in and liver of mouse upon oxidative stress promoted by PQ, the levels of Trx and Grx mRNA species The of Trx1 in vivo studies reported that oxidative expression of Trx1 gene in Y. Y. K. Yodoi J. PubMed Scopus Google Scholar, Y. Hirota K. H. K. T. M. Yodoi J. Lett. PubMed Scopus Google Scholar, A. N. N. Maeda K. T. H. Biol. 1999; PubMed Scopus Google Scholar). is to in to the and in vivo the Trx1 mRNA in the of oxidative stress, the expression of Trx1 gene in liver and and Trx1 up-regulation as a PubMed Scopus Google Scholar). the of mouse in control both TrxR1 and mRNA levels should to the of Trxs and Grxs under oxidative stress here for the first the absolute expression patterns of transcripts coding for all known proteins of the Trx and Grx in in relation to adult embryonic stages, mRNA and oxidative stress have been Further insights into the roles of these two redox systems should be gained from the of the mechanisms underlying the vast differences here at the transcript level. The novel reported here be of in these and for the quantitation of in transcript levels as factor in different pathological