| Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis. | |
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MedLine Citation:
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PMID: 20956556 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis. |
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Authors:
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Heather L Armata; Diane Golebiowski; Dae Young Jung; Hwi Jin Ko; Jason K Kim; Hayla K Sluss |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-18 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 30 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2011-01-13 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 5787-94 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antioxidants / metabolism Ataxia Telangiectasia / genetics, pathology, physiopathology Cell Cycle Proteins / genetics, metabolism Glucose / metabolism* Heat-Shock Proteins / genetics, metabolism Homeostasis / physiology* Humans Insulin / metabolism Insulin Resistance Mice Mice, Inbred C57BL Mutation Proteins / genetics, metabolism Reactive Oxygen Species / metabolism Signal Transduction / physiology Tumor Suppressor Protein p53 / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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DK32520/DK/NIDDK NIH HHS; DK80756/DK/NIDDK NIH HHS; P30 DK32520/DK/NIDDK NIH HHS; R01 DK080756-04/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antioxidants; 0/Cell Cycle Proteins; 0/Heat-Shock Proteins; 0/Proteins; 0/Reactive Oxygen Species; 0/SESN3 protein, mouse; 0/Tumor Suppressor Protein p53; 0/sestrin 1 protein, mouse; 0/sestrin 2 protein, mouse; 11061-68-0/Insulin; 50-99-7/Glucose |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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