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Glutaredoxin-1 Silencing Induces Cell Senescence via p53/p21/p16 Signaling Axis.

Identifieur interne : 000259 ( Main/Exploration ); précédent : 000258; suivant : 000260

Glutaredoxin-1 Silencing Induces Cell Senescence via p53/p21/p16 Signaling Axis.

Auteurs : Fan Yang [République populaire de Chine] ; Meiqi Yi [République populaire de Chine] ; Yan Liu [République populaire de Chine] ; Qingtao Wang [République populaire de Chine] ; Yadong Hu [République populaire de Chine] ; Haiteng Deng [République populaire de Chine]

Source :

RBID : pubmed:29356545

Descripteurs français

English descriptors

Abstract

Glutaredoxin-1 (Grx1) catalyzes deglutathionylation with glutathione as a cofactor. Accumulating evidence indicates important roles for Grx1 and S-glutathionylation in the aging process; however, further exploration of Grx1-regulated cellular processes is important to understand the functions of Grx1 in aging. In the present study, we constructed stable Grx1 knockdown or overexpression human cell lines. Grx1 silencing significantly decreased the cellular ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) (GSH/GSSG ratio), resulting in excessive reactive oxygen species (ROS) accumulation, whereas Grx1 overexpression decreased cellular ROS levels. Grx1 silencing also increased glutathionylation of DJ-1 and HSP60, contributing to decreased mitochondrial spare respiration capacity and ATP production. We applied quantitative proteomics to identify differentially expressed proteins between Grx1 knockdown and control cells and showed that Grx1 silencing inactivated DNA replication and damage repair pathways. p53 signaling was activated by Grx1 silencing, which inhibited the CDK4-mediated G1-S transition, resulting in G1 phase cell-cycle arrest and cell senescence, a known hallmark of aging. Taken together, our results indicate that Grx1 regulates DNA replication and damage repair processes and is a potential therapeutic target for aging-related diseases.

DOI: 10.1021/acs.jproteome.7b00761
PubMed: 29356545


Affiliations:


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<keywords scheme="KwdEn" xml:lang="en">
<term>Cell Line, Tumor (MeSH)</term>
<term>Cellular Senescence (genetics)</term>
<term>Cyclin-Dependent Kinase Inhibitor p16 (genetics)</term>
<term>Cyclin-Dependent Kinase Inhibitor p16 (metabolism)</term>
<term>Cyclin-Dependent Kinase Inhibitor p21 (genetics)</term>
<term>Cyclin-Dependent Kinase Inhibitor p21 (metabolism)</term>
<term>DNA Damage (MeSH)</term>
<term>DNA Repair (drug effects)</term>
<term>Gene Expression Regulation (MeSH)</term>
<term>Glutaredoxins (antagonists & inhibitors)</term>
<term>Glutaredoxins (genetics)</term>
<term>Glutaredoxins (metabolism)</term>
<term>Glutathione (metabolism)</term>
<term>HEK293 Cells (MeSH)</term>
<term>Hep G2 Cells (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Hydrogen Peroxide (pharmacology)</term>
<term>Metabolome (drug effects)</term>
<term>Neuroglia (cytology)</term>
<term>Neuroglia (drug effects)</term>
<term>Neuroglia (metabolism)</term>
<term>Oxidation-Reduction (MeSH)</term>
<term>Oxidative Stress (MeSH)</term>
<term>Oxygen Consumption (drug effects)</term>
<term>Proteome (genetics)</term>
<term>Proteome (metabolism)</term>
<term>RNA, Small Interfering (genetics)</term>
<term>RNA, Small Interfering (metabolism)</term>
<term>Reactive Oxygen Species (metabolism)</term>
<term>Signal Transduction (MeSH)</term>
<term>Tumor Suppressor Protein p53 (genetics)</term>
<term>Tumor Suppressor Protein p53 (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Altération de l'ADN (MeSH)</term>
<term>Cellules HEK293 (MeSH)</term>
<term>Cellules HepG2 (MeSH)</term>
<term>Consommation d'oxygène (effets des médicaments et des substances chimiques)</term>
<term>Espèces réactives de l'oxygène (métabolisme)</term>
<term>Glutarédoxines (antagonistes et inhibiteurs)</term>
<term>Glutarédoxines (génétique)</term>
<term>Glutarédoxines (métabolisme)</term>
<term>Glutathion (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Inhibiteur p16 de kinase cycline-dépendante (génétique)</term>
<term>Inhibiteur p16 de kinase cycline-dépendante (métabolisme)</term>
<term>Inhibiteur p21 de kinase cycline-dépendante (génétique)</term>
<term>Inhibiteur p21 de kinase cycline-dépendante (métabolisme)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Métabolome (effets des médicaments et des substances chimiques)</term>
<term>Névroglie (cytologie)</term>
<term>Névroglie (effets des médicaments et des substances chimiques)</term>
<term>Névroglie (métabolisme)</term>
<term>Oxydoréduction (MeSH)</term>
<term>Peroxyde d'hydrogène (pharmacologie)</term>
<term>Petit ARN interférent (génétique)</term>
<term>Petit ARN interférent (métabolisme)</term>
<term>Protéine p53 suppresseur de tumeur (génétique)</term>
<term>Protéine p53 suppresseur de tumeur (métabolisme)</term>
<term>Protéome (génétique)</term>
<term>Protéome (métabolisme)</term>
<term>Régulation de l'expression des gènes (MeSH)</term>
<term>Réparation de l'ADN (effets des médicaments et des substances chimiques)</term>
<term>Stress oxydatif (MeSH)</term>
<term>Transduction du signal (MeSH)</term>
<term>Vieillissement de la cellule (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en">
<term>Glutaredoxins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>Cyclin-Dependent Kinase Inhibitor p16</term>
<term>Cyclin-Dependent Kinase Inhibitor p21</term>
<term>Glutaredoxins</term>
<term>Proteome</term>
<term>RNA, Small Interfering</term>
<term>Tumor Suppressor Protein p53</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Glutarédoxines</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr">
<term>Névroglie</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en">
<term>Neuroglia</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>DNA Repair</term>
<term>Metabolome</term>
<term>Neuroglia</term>
<term>Oxygen Consumption</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr">
<term>Consommation d'oxygène</term>
<term>Métabolome</term>
<term>Névroglie</term>
<term>Réparation de l'ADN</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Cellular Senescence</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Glutarédoxines</term>
<term>Inhibiteur p16 de kinase cycline-dépendante</term>
<term>Inhibiteur p21 de kinase cycline-dépendante</term>
<term>Petit ARN interférent</term>
<term>Protéine p53 suppresseur de tumeur</term>
<term>Protéome</term>
<term>Vieillissement de la cellule</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Cyclin-Dependent Kinase Inhibitor p16</term>
<term>Cyclin-Dependent Kinase Inhibitor p21</term>
<term>Glutaredoxins</term>
<term>Glutathione</term>
<term>Neuroglia</term>
<term>Proteome</term>
<term>RNA, Small Interfering</term>
<term>Reactive Oxygen Species</term>
<term>Tumor Suppressor Protein p53</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Espèces réactives de l'oxygène</term>
<term>Glutarédoxines</term>
<term>Glutathion</term>
<term>Inhibiteur p16 de kinase cycline-dépendante</term>
<term>Inhibiteur p21 de kinase cycline-dépendante</term>
<term>Névroglie</term>
<term>Petit ARN interférent</term>
<term>Protéine p53 suppresseur de tumeur</term>
<term>Protéome</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Peroxyde d'hydrogène</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Hydrogen Peroxide</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Cell Line, Tumor</term>
<term>DNA Damage</term>
<term>Gene Expression Regulation</term>
<term>HEK293 Cells</term>
<term>Hep G2 Cells</term>
<term>Humans</term>
<term>Oxidation-Reduction</term>
<term>Oxidative Stress</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Altération de l'ADN</term>
<term>Cellules HEK293</term>
<term>Cellules HepG2</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Oxydoréduction</term>
<term>Régulation de l'expression des gènes</term>
<term>Stress oxydatif</term>
<term>Transduction du signal</term>
</keywords>
</textClass>
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<front>
<div type="abstract" xml:lang="en">Glutaredoxin-1 (Grx1) catalyzes deglutathionylation with glutathione as a cofactor. Accumulating evidence indicates important roles for Grx1 and S-glutathionylation in the aging process; however, further exploration of Grx1-regulated cellular processes is important to understand the functions of Grx1 in aging. In the present study, we constructed stable Grx1 knockdown or overexpression human cell lines. Grx1 silencing significantly decreased the cellular ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) (GSH/GSSG ratio), resulting in excessive reactive oxygen species (ROS) accumulation, whereas Grx1 overexpression decreased cellular ROS levels. Grx1 silencing also increased glutathionylation of DJ-1 and HSP60, contributing to decreased mitochondrial spare respiration capacity and ATP production. We applied quantitative proteomics to identify differentially expressed proteins between Grx1 knockdown and control cells and showed that Grx1 silencing inactivated DNA replication and damage repair pathways. p53 signaling was activated by Grx1 silencing, which inhibited the CDK4-mediated G1-S transition, resulting in G1 phase cell-cycle arrest and cell senescence, a known hallmark of aging. Taken together, our results indicate that Grx1 regulates DNA replication and damage repair processes and is a potential therapeutic target for aging-related diseases.</div>
</front>
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<DateRevised>
<Year>2018</Year>
<Month>09</Month>
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<ISSN IssnType="Electronic">1535-3907</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>17</Volume>
<Issue>3</Issue>
<PubDate>
<Year>2018</Year>
<Month>03</Month>
<Day>02</Day>
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<Title>Journal of proteome research</Title>
<ISOAbbreviation>J Proteome Res</ISOAbbreviation>
</Journal>
<ArticleTitle>Glutaredoxin-1 Silencing Induces Cell Senescence via p53/p21/p16 Signaling Axis.</ArticleTitle>
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</Pagination>
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<Abstract>
<AbstractText>Glutaredoxin-1 (Grx1) catalyzes deglutathionylation with glutathione as a cofactor. Accumulating evidence indicates important roles for Grx1 and S-glutathionylation in the aging process; however, further exploration of Grx1-regulated cellular processes is important to understand the functions of Grx1 in aging. In the present study, we constructed stable Grx1 knockdown or overexpression human cell lines. Grx1 silencing significantly decreased the cellular ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) (GSH/GSSG ratio), resulting in excessive reactive oxygen species (ROS) accumulation, whereas Grx1 overexpression decreased cellular ROS levels. Grx1 silencing also increased glutathionylation of DJ-1 and HSP60, contributing to decreased mitochondrial spare respiration capacity and ATP production. We applied quantitative proteomics to identify differentially expressed proteins between Grx1 knockdown and control cells and showed that Grx1 silencing inactivated DNA replication and damage repair pathways. p53 signaling was activated by Grx1 silencing, which inhibited the CDK4-mediated G1-S transition, resulting in G1 phase cell-cycle arrest and cell senescence, a known hallmark of aging. Taken together, our results indicate that Grx1 regulates DNA replication and damage repair processes and is a potential therapeutic target for aging-related diseases.</AbstractText>
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<LastName>Yang</LastName>
<ForeName>Fan</ForeName>
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<ForeName>Yan</ForeName>
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<ForeName>Qingtao</ForeName>
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<Affiliation>Beijing Chaoyang Hospital Affiliated to Capital Medical University , Chaoyang District, Beijing 100020, China.</Affiliation>
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<Affiliation>MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University , Beijing 100084, China.</Affiliation>
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<AffiliationInfo>
<Affiliation>Chengdu Institute of Biology, Chinese Academy of Sciences , Renmin South Road, Chengdu 610000, China.</Affiliation>
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<ForeName>Haiteng</ForeName>
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<Affiliation>MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University , Beijing 100084, China.</Affiliation>
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<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
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<Country>United States</Country>
<MedlineTA>J Proteome Res</MedlineTA>
<NlmUniqueID>101128775</NlmUniqueID>
<ISSNLinking>1535-3893</ISSNLinking>
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<DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
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<DescriptorName UI="D016922" MajorTopicYN="N">Cellular Senescence</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D019941" MajorTopicYN="N">Cyclin-Dependent Kinase Inhibitor p16</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
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<DescriptorName UI="D050759" MajorTopicYN="N">Cyclin-Dependent Kinase Inhibitor p21</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
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<DescriptorName UI="D004260" MajorTopicYN="N">DNA Repair</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
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<MeshHeading>
<DescriptorName UI="D005786" MajorTopicYN="N">Gene Expression Regulation</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D054477" MajorTopicYN="N">Glutaredoxins</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D005978" MajorTopicYN="N">Glutathione</DescriptorName>
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<QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
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<MeshHeading>
<DescriptorName UI="D010084" MajorTopicYN="N">Oxidation-Reduction</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D034741" MajorTopicYN="N">RNA, Small Interfering</DescriptorName>
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<DescriptorName UI="D017382" MajorTopicYN="N">Reactive Oxygen Species</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D016159" MajorTopicYN="N">Tumor Suppressor Protein p53</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM">
<Keyword MajorTopicYN="Y">Glutaredoxin-1</Keyword>
<Keyword MajorTopicYN="Y">S-glutathionylation</Keyword>
<Keyword MajorTopicYN="Y">cell senescence</Keyword>
<Keyword MajorTopicYN="Y">proteomics</Keyword>
<Keyword MajorTopicYN="Y">redox signaling</Keyword>
</KeywordList>
</MedlineCitation>
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<Year>2018</Year>
<Month>1</Month>
<Day>23</Day>
<Hour>6</Hour>
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<PubMedPubDate PubStatus="medline">
<Year>2018</Year>
<Month>9</Month>
<Day>18</Day>
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<Year>2018</Year>
<Month>1</Month>
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<ArticleId IdType="pubmed">29356545</ArticleId>
<ArticleId IdType="doi">10.1021/acs.jproteome.7b00761</ArticleId>
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<country>
<li>République populaire de Chine</li>
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<settlement>
<li>Pékin</li>
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<country name="République populaire de Chine">
<noRegion>
<name sortKey="Yang, Fan" sort="Yang, Fan" uniqKey="Yang F" first="Fan" last="Yang">Fan Yang</name>
</noRegion>
<name sortKey="Deng, Haiteng" sort="Deng, Haiteng" uniqKey="Deng H" first="Haiteng" last="Deng">Haiteng Deng</name>
<name sortKey="Hu, Yadong" sort="Hu, Yadong" uniqKey="Hu Y" first="Yadong" last="Hu">Yadong Hu</name>
<name sortKey="Hu, Yadong" sort="Hu, Yadong" uniqKey="Hu Y" first="Yadong" last="Hu">Yadong Hu</name>
<name sortKey="Liu, Yan" sort="Liu, Yan" uniqKey="Liu Y" first="Yan" last="Liu">Yan Liu</name>
<name sortKey="Wang, Qingtao" sort="Wang, Qingtao" uniqKey="Wang Q" first="Qingtao" last="Wang">Qingtao Wang</name>
<name sortKey="Yi, Meiqi" sort="Yi, Meiqi" uniqKey="Yi M" first="Meiqi" last="Yi">Meiqi Yi</name>
</country>
</tree>
</affiliations>
</record>

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