| Early onset senescence occurs when fibroblasts lack the glutamate-cysteine ligase modifier subunit. | |
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MedLine Citation:
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PMID: 19427898 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cellular senescence is the irreversible entry of cells into growth arrest. Senescence of primary cells in culture has long been used as an in vitro model for aging. Glutamate-cysteine ligase (GCL) controls the synthetic rate of the important cellular antioxidant glutathione (GSH). The catalytic subunit of GCL, GCLC, is catalytically active and essential for life. By contrast the modifier subunit of GCL, GCLM, is dispensable in mice. Although it is recognized that GCLM increases the rate of GSH synthesis, its physiological role is unclear. Herein, we show that loss of Gclm leads to premature senescence of primary murine fibroblasts as characterized by: (a) diminished growth rate, (b) cell morphology consistent with senescence, (c) increases in senescence-associated beta-galactosidase activity, and (d) cell cycle arrest at the G(1)/S and G(2)/M boundaries. These changes are accompanied by increased intracellular ROS, accumulation of DNA damage, and induction of p53 and p21 proteins. We also found that N-acetylcysteine increases intracellular GSH and prevents premature senescence in Gclm(-/-) cells. These results suggest that the control of GCLM, which in turn controls aspects of the cellular redox environment via GSH, is important in determining the replicative capacity of the cell. |
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Authors:
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Ying Chen; Elisabet Johansson; Yunxia Fan; Howard G Shertzer; Vasilis Vasiliou; Daniel W Nebert; Timothy P Dalton |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-05-08 |
Journal Detail:
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Title: Free radical biology & medicine Volume: 47 ISSN: 1873-4596 ISO Abbreviation: Free Radic. Biol. Med. Publication Date: 2009 Aug |
Date Detail:
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Created Date: 2009-07-14 Completed Date: 2010-01-14 Revised Date: 2011-05-03 |
Medline Journal Info:
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Nlm Unique ID: 8709159 Medline TA: Free Radic Biol Med Country: United States |
Other Details:
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Languages: eng Pagination: 410-8 Citation Subset: IM |
Affiliation:
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Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA. ying.chen@ucdenver.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcysteine
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pharmacology Animals Cell Aging / drug effects, genetics Cell Culture Techniques Cell Cycle / drug effects, genetics Cell Growth Processes / drug effects, genetics Cyclin-Dependent Kinase Inhibitor p21 / genetics, metabolism DNA Damage Female Fetus Fibroblasts / metabolism*, pathology Free Radical Scavengers / pharmacology Glutamate-Cysteine Ligase / genetics, metabolism* Glutathione / metabolism Mice Mice, Inbred C57BL Mice, Knockout Pregnancy Protein Subunits / genetics, metabolism* Reactive Oxygen Species / metabolism Tumor Suppressor Protein p53 / genetics, metabolism beta-Galactosidase / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P30 ES006096-10S19007/ES/NIEHS NIH HHS; P30 ES006096-159007/ES/NIEHS NIH HHS; P30 ES06096/ES/NIEHS NIH HHS; R01 ES012463/ES/NIEHS NIH HHS; R01 ES012463-01/ES/NIEHS NIH HHS; R01 ES012463-02/ES/NIEHS NIH HHS; R01 ES012463-03/ES/NIEHS NIH HHS; R01 ES012463-04/ES/NIEHS NIH HHS; R01 ES012463-05/ES/NIEHS NIH HHS; R01 EY017963/EY/NEI NIH HHS; R01 EY017963-01A1/EY/NEI NIH HHS; R01 EY017963-02/EY/NEI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cyclin-Dependent Kinase Inhibitor p21; 0/Free Radical Scavengers; 0/Protein Subunits; 0/Reactive Oxygen Species; 0/Tumor Suppressor Protein p53; 616-91-1/Acetylcysteine; 70-18-8/Glutathione; EC 3.2.1.23/beta-Galactosidase; EC 6.3.2.2/Glutamate-Cysteine Ligase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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