Phosphorylation of HuR by Chk2 Regulates SIRT1 Expression
The RNA binding protein HuR regulates the stability of many target mRNAs. Here, we report that HuR associated with the 3′ untranslated region of the mRNA encoding the longevity and stress-response protein SIRT1, stabilized the SIRT1 mRNA, and increased SIRT1 expression levels. Unexpectedly, oxidativ...
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| Veröffentlicht in: | Molecular cell 2007-02, Vol.25 (4), p.543-557 |
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| creator | Abdelmohsen, Kotb Pullmann, Rudolf Lal, Ashish Kim, Hyeon Ho Galban, Stefanie Yang, Xiaoling Blethrow, Justin D. Walker, Mark Shubert, Jonathan Gillespie, David A. Furneaux, Henry Gorospe, Myriam |
| description | The RNA binding protein HuR regulates the stability of many target mRNAs. Here, we report that HuR associated with the 3′ untranslated region of the mRNA encoding the longevity and stress-response protein SIRT1, stabilized the SIRT1 mRNA, and increased SIRT1 expression levels. Unexpectedly, oxidative stress triggered the dissociation of the [HuR-SIRT1 mRNA] complex, in turn promoting SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival. The cell cycle checkpoint kinase Chk2 was activated by H
2O
2, interacted with HuR, and was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of these residues revealed a complex pattern of HuR binding, with S100 appearing to be important for [HuR-SIRT1 mRNA] dissociation after H
2O
2. Our findings demonstrate that HuR regulates SIRT1 expression, underscore functional links between the two stress-response proteins, and implicate Chk2 in these processes. |
| doi_str_mv | 10.1016/j.molcel.2007.01.011 |
| format | Article |
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2O
2, interacted with HuR, and was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of these residues revealed a complex pattern of HuR binding, with S100 appearing to be important for [HuR-SIRT1 mRNA] dissociation after H
2O
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2O
2, interacted with HuR, and was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of these residues revealed a complex pattern of HuR binding, with S100 appearing to be important for [HuR-SIRT1 mRNA] dissociation after H
2O
2. Our findings demonstrate that HuR regulates SIRT1 expression, underscore functional links between the two stress-response proteins, and implicate Chk2 in these processes.</description><subject>Antigens, Surface - metabolism</subject><subject>Base Sequence</subject><subject>Cellular Senescence - drug effects</subject><subject>Checkpoint Kinase 2</subject><subject>ELAV Proteins</subject><subject>ELAV-Like Protein 1</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - enzymology</subject><subject>Gene Expression Regulation - drug effects</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Molecular Sequence Data</subject><subject>Oxidative Stress - drug effects</subject><subject>Phosphorylation - drug effects</subject><subject>Point Mutation - genetics</subject><subject>Protein Binding - drug effects</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Ribonucleoproteins - metabolism</subject><subject>RNA</subject><subject>RNA Stability - drug effects</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Sirtuin 1</subject><subject>Sirtuins - genetics</subject><subject>Sirtuins - metabolism</subject><subject>Substrate Specificity - drug effects</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kFFLwzAQx4Mobk6_gUiffNvMtWnTvAgyphsIypzPIU3TNbNrZtIO9-3NWHH64nFwgfvf_y4_hK4BjwBDcrcarU0lVTUKMaYjDD7hBPUBMzokkJDT7h3SJO6hC-dWGAOJU3aOekAjoElI-4i9lsZtSmN3lWi0qQNTBNN2HmS7YFx-hMFcLVvfUS54m80XEEy-NlY555WX6KwQlVNXXR2g98fJYjwdPr88zcYPz0MZh7QZKkhTKXFSAKaEFEWWRUTksY8sDOMoLpIwwzIDYIThPC3yXEiR-5sly4AKEQ3Q_cF302ZrlUtVN1ZUfGP1WtgdN0Lzv51al3xpthxYmlCCvcFtZ2DNZ6tcw9faeXCVqJVpHU8YjmLGiBeSg1Ba45xVxc8SwHzPnK_4gTnfM-cYfIIfu_l94HGog3z8gfKYtlpZ7qRWtVS5tko2PDf6_w3fzXKVEA</recordid><startdate>20070223</startdate><enddate>20070223</enddate><creator>Abdelmohsen, Kotb</creator><creator>Pullmann, Rudolf</creator><creator>Lal, Ashish</creator><creator>Kim, Hyeon Ho</creator><creator>Galban, Stefanie</creator><creator>Yang, Xiaoling</creator><creator>Blethrow, Justin D.</creator><creator>Walker, Mark</creator><creator>Shubert, Jonathan</creator><creator>Gillespie, David A.</creator><creator>Furneaux, Henry</creator><creator>Gorospe, Myriam</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20070223</creationdate><title>Phosphorylation of HuR by Chk2 Regulates SIRT1 Expression</title><author>Abdelmohsen, Kotb ; 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Here, we report that HuR associated with the 3′ untranslated region of the mRNA encoding the longevity and stress-response protein SIRT1, stabilized the SIRT1 mRNA, and increased SIRT1 expression levels. Unexpectedly, oxidative stress triggered the dissociation of the [HuR-SIRT1 mRNA] complex, in turn promoting SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival. The cell cycle checkpoint kinase Chk2 was activated by H
2O
2, interacted with HuR, and was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of these residues revealed a complex pattern of HuR binding, with S100 appearing to be important for [HuR-SIRT1 mRNA] dissociation after H
2O
2. Our findings demonstrate that HuR regulates SIRT1 expression, underscore functional links between the two stress-response proteins, and implicate Chk2 in these processes.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17317627</pmid><doi>10.1016/j.molcel.2007.01.011</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| source | Elsevier ScienceDirect Journals Complete - AutoHoldings; MEDLINE; Cell Press Free Archives; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Antigens, Surface - metabolism Base Sequence Cellular Senescence - drug effects Checkpoint Kinase 2 ELAV Proteins ELAV-Like Protein 1 Fibroblasts - drug effects Fibroblasts - enzymology Gene Expression Regulation - drug effects HeLa Cells Humans Hydrogen Peroxide - pharmacology Molecular Sequence Data Oxidative Stress - drug effects Phosphorylation - drug effects Point Mutation - genetics Protein Binding - drug effects Protein-Serine-Threonine Kinases - metabolism Ribonucleoproteins - metabolism RNA RNA Stability - drug effects RNA, Messenger - genetics RNA, Messenger - metabolism RNA-Binding Proteins - metabolism Sirtuin 1 Sirtuins - genetics Sirtuins - metabolism Substrate Specificity - drug effects |
| title | Phosphorylation of HuR by Chk2 Regulates SIRT1 Expression |
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