| Inhibition of wild-type p66ShcA in mesangial cells prevents glycooxidant-dependent FOXO3a regulation and promotes the survival phenotype. | |
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MedLine Citation:
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PMID: 17077388 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hyperglycemia triggers an exponential increase in reactive oxygen species (ROS) at the cellular level. Here, we demonstrate induction of the oxidant-resistant phenotype in mesangial cells by silencing the wild-type (WT) p66ShcA gene. Two approaches were employed to inhibit WTp66ShcA in SV40 murine mesangial cells and normal human mesangial cells: transient transfection with isoform-specific p66ShcA short-intervening RNA and stable transfection with mutant 36 p66ShcA expression vector. At high ambient glucose (HG), p66ShcA-deficient cells exhibit resistance to HG-induced ROS generation and attenuation in the amplitude of the kinetic curves for intracellular ROS metabolism, indicative of the pivotal role of WTp66ShcA in the generation of HG oxidant stress. We next examined phosphorylation and subcellular distribution of FKHRL1 (FOXO3a), a potent stress response regulator and downstream target of WTp66ShcA redox function. At HG, cell extracts of p66ShcA-deficient cells analyzed by immunoblotting show attenuation of FOXO3a phosphorylation at Thr-32, and indirect immunofluorescence of p66ShcA-deficient cells, cotransfected with HA-FOXO3a, show predominant HA-FOXO3a nuclear localization. Conversely, parental cells at HG show upregulation of phos-Thr-32 and nuclear export of HA-FOXO3a. To determine whether inhibition of cross talk between WTp66ShcA and FOXO3a confers protection against oxidant-induced DNA damage, DNA strand breaks (DSB) and apoptosis were examined. At HG, p66ShcA-deficient cells exhibit increased resistance to DSB and apoptosis, while parental cells show a striking increase in both parameters. We conclude that knockdown of WTp66ShcA redox function prevents HG-dependent FOXO3a regulation and promotes the survival phenotype. |
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Authors:
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Janaki Chintapalli; Shuo Yang; David Opawumi; Sunita Ray Goyal; Nazia Shamsuddin; Ashwani Malhotra; Krzysztof Reiss; Leonard G Meggs |
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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: 2006-10-31 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 292 ISSN: 1931-857X ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2007 Feb |
Date Detail:
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Created Date: 2007-02-06 Completed Date: 2007-03-27 Revised Date: 2011-04-28 |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: United States |
Other Details:
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Languages: eng Pagination: F523-30 Citation Subset: IM |
Affiliation:
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Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, Pennsylvania, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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antagonists & inhibitors*,
genetics Animals Cells, Cultured Forkhead Transcription Factors / antagonists & inhibitors, physiology* Gene Expression Regulation / drug effects Glucose / pharmacology Humans Mesangial Cells / drug effects*, physiology* Mice Phenotype RNA, Small Interfering / pharmacology Reactive Oxygen Species / metabolism Shc Signaling Adaptor Proteins Transfection |
| Grant Support | |
ID/Acronym/Agency:
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1R01-CA/NS-95518/CA/NCI NIH HHS; 1R01-HL072852/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/FOXO3 protein, human; 0/Forkhead Transcription Factors; 0/RNA, Small Interfering; 0/Reactive Oxygen Species; 0/SHC1 protein, human; 0/Shc Signaling Adaptor Proteins; 0/Shc1 protein, mouse; 50-99-7/Glucose |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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