| SIRT1 Deficiency Downregulates PTEN/JNK/FOXO1 Pathway to Block Reactive Oxygen Species-Induced Apoptosis in Mouse Embryonic Stem Cells. | |
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MedLine Citation:
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PMID: 21083429 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Silent mating type information regulation 2 homolog 1 (SIRT1) plays a critical role in reactive oxygen species-triggered apoptosis in mouse embryonic stem (mES) cells. Here, we investigated a possible role for the PTEN/Akt/JNK pathway in the SIRT1-mediated apoptosis pathway in mES cells. Akt was activated by removal of anti-oxidant 2-mercaptoethanol in SIRT1(-/-) mES cells. Since PTEN is a negative regulator of Akt and its activity can be modulated by acetylation, we investigated if SIRT1 deacetylated PTEN to downregulate Akt to trigger apoptosis in anti-oxidant-free culture conditions. PTEN was hyperacetylated and excluded from the nucleus in SIRT1(-/-) mES cells, consistent with enhanced Akt activity. SIRT1 deficiency enhanced the acetylation/phosphorylation level of FOXO1 and subsequently inhibited the nuclear localization of FOXO1. Cellular acetylation levels were enhanced by DNA-damaging agent, not by removal of anti-oxidant. c-Jun NH2-terminal kinase (JNK) was activated by removal of anti-oxidant in SIRT1-dependent manner. Although p53 acetylation was stronger in SIRT1(-/-) mES cells, DNA-damaging stress activated phosphorylation and enhanced cellular levels of p53 irrespective of SIRT1, whereas removal of anti-oxidant slightly activated p53 only with SIRT1. Expression levels of Bim and Puma were increased in anti-oxidant-free culture conditions in an SIRT1-dependent manner and treatment with JNK inhibitor blocked induction of Bim expression. DNA-damaging agent activated caspase3 regardless of SIRT1. Our data support an important role for SIRT1 in preparing the PTEN/JNK/FOXO1 pathway to respond to cellular reactive oxygen species. |
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Authors:
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Hee-Don Chae; Hal E Broxmeyer |
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Publication Detail:
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Type: Journal Article Date: 2011-01-03 |
Journal Detail:
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Title: Stem cells and development Volume: 20 ISSN: 1557-8534 ISO Abbreviation: Stem Cells Dev. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101197107 Medline TA: Stem Cells Dev Country: United States |
Other Details:
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Languages: eng Pagination: 1277-85 Citation Subset: IM |
Affiliation:
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Department of Microbiology and Immunology, Indiana University School of Medicine , Indianapolis, Indiana. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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