Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase.
Identifieur interne : 000358 ( Main/Exploration ); précédent : 000357; suivant : 000359Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase.
Auteurs : Justin R. Prigge [États-Unis] ; Lucia Coppo [Suède] ; Sebastin S. Martin [Suède] ; Fernando Ogata [Suède] ; Colin G. Miller [États-Unis] ; Michael D. Bruschwein [États-Unis] ; David J. Orlicky [États-Unis] ; Colin T. Shearn [États-Unis] ; Jean A. Kundert [États-Unis] ; Julia Lytchier [Suède] ; Alix E. Herr [États-Unis] ; Se Mattsson [Suède] ; Matthew P. Taylor [États-Unis] ; Tomas N. Gustafsson [Suède] ; Elias S J. Arnér [Suède] ; Arne Holmgren [Suède] ; Edward E. Schmidt [États-Unis]Source :
- Cell reports [ 2211-1247 ] ; 2017.
Descripteurs français
- KwdFr :
- MESH :
- cytologie : Hépatocytes.
- métabolisme : Glutathione reductase, Hépatocytes, Thioredoxin reductase 1, Thiorédoxines.
- physiologie : Prolifération cellulaire.
- Animaux, Humains, Mâle, Souris.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Glutathione Reductase, Thioredoxin Reductase 1, Thioredoxins.
- cytology : Hepatocytes.
- metabolism : Hepatocytes.
- physiology : Cell Proliferation.
- Animals, Humans, Male, Mice.
Abstract
Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP+ ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triple-null) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.
DOI: 10.1016/j.celrep.2017.06.019
PubMed: 28658624
PubMed Central: PMC5730093
Affiliations:
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Bruschwein</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Orlicky, David J" sort="Orlicky, David J" uniqKey="Orlicky D" first="David J" last="Orlicky">David J. Orlicky</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Colorado Anschutz Medical Center, Denver, CO 80045</wicri:regionArea><placeName><region type="state">Colorado</region></placeName></affiliation></author><author><name sortKey="Shearn, Colin T" sort="Shearn, Colin T" uniqKey="Shearn C" first="Colin T" last="Shearn">Colin T. Shearn</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Center, Denver, CO 80045</wicri:regionArea><placeName><region type="state">Colorado</region></placeName></affiliation></author><author><name sortKey="Kundert, Jean A" sort="Kundert, Jean A" uniqKey="Kundert J" first="Jean A" last="Kundert">Jean A. Kundert</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Lytchier, Julia" sort="Lytchier, Julia" uniqKey="Lytchier J" first="Julia" last="Lytchier">Julia Lytchier</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Herr, Alix E" sort="Herr, Alix E" uniqKey="Herr A" first="Alix E" last="Herr">Alix E. Herr</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Mattsson, Se" sort="Mattsson, Se" uniqKey="Mattsson " first=" Se" last="Mattsson"> Se Mattsson</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Taylor, Matthew P" sort="Taylor, Matthew P" uniqKey="Taylor M" first="Matthew P" last="Taylor">Matthew P. Taylor</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Gustafsson, Tomas N" sort="Gustafsson, Tomas N" uniqKey="Gustafsson T" first="Tomas N" last="Gustafsson">Tomas N. Gustafsson</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Clinical Bacteriology, Sunderby Research Unit, Umeå University, 901 85 Umeå, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Clinical Bacteriology, Sunderby Research Unit, Umeå University, 901 85 Umeå</wicri:regionArea><wicri:noRegion>901 85 Umeå</wicri:noRegion></affiliation></author><author><name sortKey="Arner, Elias S J" sort="Arner, Elias S J" uniqKey="Arner E" first="Elias S J" last="Arnér">Elias S J. Arnér</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Holmgren, Arne" sort="Holmgren, Arne" uniqKey="Holmgren A" first="Arne" last="Holmgren">Arne Holmgren</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Schmidt, Edward E" sort="Schmidt, Edward E" uniqKey="Schmidt E" first="Edward E" last="Schmidt">Edward E. Schmidt</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA. Electronic address: eschmidt@montana.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28658624</idno><idno type="pmid">28658624</idno><idno type="doi">10.1016/j.celrep.2017.06.019</idno><idno type="pmc">PMC5730093</idno><idno type="wicri:Area/Main/Corpus">000328</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000328</idno><idno type="wicri:Area/Main/Curation">000328</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000328</idno><idno type="wicri:Area/Main/Exploration">000328</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase.</title><author><name sortKey="Prigge, Justin R" sort="Prigge, Justin R" uniqKey="Prigge J" first="Justin R" last="Prigge">Justin R. Prigge</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Coppo, Lucia" sort="Coppo, Lucia" uniqKey="Coppo L" first="Lucia" last="Coppo">Lucia Coppo</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Martin, Sebastin S" sort="Martin, Sebastin S" uniqKey="Martin S" first="Sebastin S" last="Martin">Sebastin S. Martin</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Ogata, Fernando" sort="Ogata, Fernando" uniqKey="Ogata F" first="Fernando" last="Ogata">Fernando Ogata</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Miller, Colin G" sort="Miller, Colin G" uniqKey="Miller C" first="Colin G" last="Miller">Colin G. Miller</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Bruschwein, Michael D" sort="Bruschwein, Michael D" uniqKey="Bruschwein M" first="Michael D" last="Bruschwein">Michael D. Bruschwein</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Orlicky, David J" sort="Orlicky, David J" uniqKey="Orlicky D" first="David J" last="Orlicky">David J. Orlicky</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Colorado Anschutz Medical Center, Denver, CO 80045</wicri:regionArea><placeName><region type="state">Colorado</region></placeName></affiliation></author><author><name sortKey="Shearn, Colin T" sort="Shearn, Colin T" uniqKey="Shearn C" first="Colin T" last="Shearn">Colin T. Shearn</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Center, Denver, CO 80045</wicri:regionArea><placeName><region type="state">Colorado</region></placeName></affiliation></author><author><name sortKey="Kundert, Jean A" sort="Kundert, Jean A" uniqKey="Kundert J" first="Jean A" last="Kundert">Jean A. Kundert</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Lytchier, Julia" sort="Lytchier, Julia" uniqKey="Lytchier J" first="Julia" last="Lytchier">Julia Lytchier</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Herr, Alix E" sort="Herr, Alix E" uniqKey="Herr A" first="Alix E" last="Herr">Alix E. Herr</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Mattsson, Se" sort="Mattsson, Se" uniqKey="Mattsson " first=" Se" last="Mattsson"> Se Mattsson</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Taylor, Matthew P" sort="Taylor, Matthew P" uniqKey="Taylor M" first="Matthew P" last="Taylor">Matthew P. Taylor</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author><author><name sortKey="Gustafsson, Tomas N" sort="Gustafsson, Tomas N" uniqKey="Gustafsson T" first="Tomas N" last="Gustafsson">Tomas N. Gustafsson</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Clinical Bacteriology, Sunderby Research Unit, Umeå University, 901 85 Umeå, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Clinical Bacteriology, Sunderby Research Unit, Umeå University, 901 85 Umeå</wicri:regionArea><wicri:noRegion>901 85 Umeå</wicri:noRegion></affiliation></author><author><name sortKey="Arner, Elias S J" sort="Arner, Elias S J" uniqKey="Arner E" first="Elias S J" last="Arnér">Elias S J. Arnér</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Holmgren, Arne" sort="Holmgren, Arne" uniqKey="Holmgren A" first="Arne" last="Holmgren">Arne Holmgren</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm</wicri:regionArea><wicri:noRegion>171 77 Stockholm</wicri:noRegion></affiliation></author><author><name sortKey="Schmidt, Edward E" sort="Schmidt, Edward E" uniqKey="Schmidt E" first="Edward E" last="Schmidt">Edward E. Schmidt</name><affiliation wicri:level="2"><nlm:affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA. Electronic address: eschmidt@montana.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Microbiology & Immunology, Montana State University, Bozeman, MT 59718</wicri:regionArea><placeName><region type="state">Montana</region></placeName></affiliation></author></analytic><series><title level="j">Cell reports</title><idno type="eISSN">2211-1247</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Cell Proliferation (physiology)</term><term>Glutathione Reductase (metabolism)</term><term>Hepatocytes (cytology)</term><term>Hepatocytes (metabolism)</term><term>Humans (MeSH)</term><term>Male (MeSH)</term><term>Mice (MeSH)</term><term>Thioredoxin Reductase 1 (metabolism)</term><term>Thioredoxins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Glutathione reductase (métabolisme)</term><term>Humains (MeSH)</term><term>Hépatocytes (cytologie)</term><term>Hépatocytes (métabolisme)</term><term>Mâle (MeSH)</term><term>Prolifération cellulaire (physiologie)</term><term>Souris (MeSH)</term><term>Thioredoxin reductase 1 (métabolisme)</term><term>Thiorédoxines (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glutathione Reductase</term><term>Thioredoxin Reductase 1</term><term>Thioredoxins</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Hépatocytes</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Hepatocytes</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Hepatocytes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glutathione reductase</term><term>Hépatocytes</term><term>Thioredoxin reductase 1</term><term>Thiorédoxines</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Prolifération cellulaire</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Cell Proliferation</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Male</term><term>Mice</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Mâle</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP<sup>+</sup> ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triple-null) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28658624</PMID><DateCompleted><Year>2018</Year><Month>04</Month><Day>20</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">2211-1247</ISSN><JournalIssue CitedMedium="Internet"><Volume>19</Volume><Issue>13</Issue><PubDate><Year>2017</Year><Month>06</Month><Day>27</Day></PubDate></JournalIssue><Title>Cell reports</Title><ISOAbbreviation>Cell Rep</ISOAbbreviation></Journal><ArticleTitle>Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase.</ArticleTitle><Pagination><MedlinePgn>2771-2781</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S2211-1247(17)30816-1</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.celrep.2017.06.019</ELocationID><Abstract><AbstractText>Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP<sup>+</sup> ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triple-null) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.</AbstractText><CopyrightInformation>Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Prigge</LastName><ForeName>Justin R</ForeName><Initials>JR</Initials><AffiliationInfo><Affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Coppo</LastName><ForeName>Lucia</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martin</LastName><ForeName>Sebastin S</ForeName><Initials>SS</Initials><AffiliationInfo><Affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ogata</LastName><ForeName>Fernando</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Miller</LastName><ForeName>Colin G</ForeName><Initials>CG</Initials><AffiliationInfo><Affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bruschwein</LastName><ForeName>Michael D</ForeName><Initials>MD</Initials><AffiliationInfo><Affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Orlicky</LastName><ForeName>David J</ForeName><Initials>DJ</Initials><AffiliationInfo><Affiliation>Department of Pathology, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shearn</LastName><ForeName>Colin T</ForeName><Initials>CT</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Center, Denver, CO 80045, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kundert</LastName><ForeName>Jean A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lytchier</LastName><ForeName>Julia</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Herr</LastName><ForeName>Alix E</ForeName><Initials>AE</Initials><AffiliationInfo><Affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mattsson</LastName><ForeName>Åse</ForeName><Initials>Å</Initials><AffiliationInfo><Affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Taylor</LastName><ForeName>Matthew P</ForeName><Initials>MP</Initials><AffiliationInfo><Affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gustafsson</LastName><ForeName>Tomas N</ForeName><Initials>TN</Initials><AffiliationInfo><Affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Clinical Bacteriology, Sunderby Research Unit, Umeå University, 901 85 Umeå, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Arnér</LastName><ForeName>Elias S J</ForeName><Initials>ESJ</Initials><AffiliationInfo><Affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Holmgren</LastName><ForeName>Arne</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schmidt</LastName><ForeName>Edward E</ForeName><Initials>EE</Initials><AffiliationInfo><Affiliation>Microbiology & Immunology, Montana State University, Bozeman, MT 59718, USA. Electronic address: eschmidt@montana.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P30 DK048520</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 GM110732</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R21 AG055022</GrantID><Acronym>AG</Acronym><Agency>NIA NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P30 DK079626</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AG040020</GrantID><Acronym>AG</Acronym><Agency>NIA NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P60 DK079626</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI055739</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Cell Rep</MedlineTA><NlmUniqueID>101573691</NlmUniqueID></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>52500-60-4</RegistryNumber><NameOfSubstance UI="D013879">Thioredoxins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.8.1.7</RegistryNumber><NameOfSubstance UI="D005980">Glutathione Reductase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.8.1.9</RegistryNumber><NameOfSubstance UI="D054481">Thioredoxin Reductase 1</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D049109" MajorTopicYN="N">Cell Proliferation</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005980" MajorTopicYN="N">Glutathione Reductase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D022781" MajorTopicYN="N">Hepatocytes</DescriptorName><QualifierName UI="Q000166" MajorTopicYN="Y">cytology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D054481" MajorTopicYN="N">Thioredoxin Reductase 1</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013879" MajorTopicYN="N">Thioredoxins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">cancer</Keyword><Keyword MajorTopicYN="Y">glutathione</Keyword><Keyword MajorTopicYN="Y">liver</Keyword><Keyword MajorTopicYN="Y">methionine cycle</Keyword><Keyword MajorTopicYN="Y">mouse model</Keyword><Keyword MajorTopicYN="Y">proliferation</Keyword><Keyword MajorTopicYN="Y">redox</Keyword><Keyword MajorTopicYN="Y">ribonucleotide reductase</Keyword><Keyword MajorTopicYN="Y">thioredoxin</Keyword><Keyword MajorTopicYN="Y">transsulfuration</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>12</Month><Day>09</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2017</Year><Month>05</Month><Day>16</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>06</Month><Day>02</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>6</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>6</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2018</Year><Month>4</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28658624</ArticleId><ArticleId IdType="pii">S2211-1247(17)30816-1</ArticleId><ArticleId IdType="doi">10.1016/j.celrep.2017.06.019</ArticleId><ArticleId IdType="pmc">PMC5730093</ArticleId><ArticleId 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Prigge</name></region><name sortKey="Bruschwein, Michael D" sort="Bruschwein, Michael D" uniqKey="Bruschwein M" first="Michael D" last="Bruschwein">Michael D. Bruschwein</name><name sortKey="Herr, Alix E" sort="Herr, Alix E" uniqKey="Herr A" first="Alix E" last="Herr">Alix E. Herr</name><name sortKey="Kundert, Jean A" sort="Kundert, Jean A" uniqKey="Kundert J" first="Jean A" last="Kundert">Jean A. Kundert</name><name sortKey="Miller, Colin G" sort="Miller, Colin G" uniqKey="Miller C" first="Colin G" last="Miller">Colin G. Miller</name><name sortKey="Orlicky, David J" sort="Orlicky, David J" uniqKey="Orlicky D" first="David J" last="Orlicky">David J. Orlicky</name><name sortKey="Schmidt, Edward E" sort="Schmidt, Edward E" uniqKey="Schmidt E" first="Edward E" last="Schmidt">Edward E. Schmidt</name><name sortKey="Shearn, Colin T" sort="Shearn, Colin T" uniqKey="Shearn C" first="Colin T" last="Shearn">Colin T. Shearn</name><name sortKey="Taylor, Matthew P" sort="Taylor, Matthew P" uniqKey="Taylor M" first="Matthew P" last="Taylor">Matthew P. Taylor</name></country><country name="Suède"><noRegion><name sortKey="Coppo, Lucia" sort="Coppo, Lucia" uniqKey="Coppo L" first="Lucia" last="Coppo">Lucia Coppo</name></noRegion><name sortKey="Arner, Elias S J" sort="Arner, Elias S J" uniqKey="Arner E" first="Elias S J" last="Arnér">Elias S J. Arnér</name><name sortKey="Gustafsson, Tomas N" sort="Gustafsson, Tomas N" uniqKey="Gustafsson T" first="Tomas N" last="Gustafsson">Tomas N. Gustafsson</name><name sortKey="Holmgren, Arne" sort="Holmgren, Arne" uniqKey="Holmgren A" first="Arne" last="Holmgren">Arne Holmgren</name><name sortKey="Lytchier, Julia" sort="Lytchier, Julia" uniqKey="Lytchier J" first="Julia" last="Lytchier">Julia Lytchier</name><name sortKey="Martin, Sebastin S" sort="Martin, Sebastin S" uniqKey="Martin S" first="Sebastin S" last="Martin">Sebastin S. Martin</name><name sortKey="Mattsson, Se" sort="Mattsson, Se" uniqKey="Mattsson " first=" Se" last="Mattsson"> Se Mattsson</name><name sortKey="Ogata, Fernando" sort="Ogata, Fernando" uniqKey="Ogata F" first="Fernando" last="Ogata">Fernando Ogata</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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