| Functional RNAi Screen Identifies System A Neutral Amino Acid Transporter 2 (SNAT2) As a Mediator of Arsenic-induced Endoplasmic Reticulum Stress. | |
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MedLine Citation:
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PMID: 22215663 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Exposure to the toxic metalloid arsenic is associated with diabetes and cancer, and causes proteotoxicity and endoplasmic reticulum (ER) stress at the cellular level. Adaptive responses to ER stress are implicated in cancer and diabetes, thus understanding mechanisms of arsenic-induced ER stress may offer insights into pathogenesis. Here, we identify genes required for arsenite-induced ER stress response in a genome-wide RNAi screen. Using a shRNA library targeting ~20,000 human genes, together with an ER stress cell model, we performed flow cytometry-based cell sorting to isolate cells with defective response to arsenite. Our screen discovered several genes modulating arsenite-induced ER stress, including sodium-dependent neutral amino acid transporter, SNAT2. SNAT2 expression and activity are upregulated by arsenite, in a manner dependent on activating transcription factor 4 (ATF4), an important mediator of the integrated stress response. Inhibition of SNAT2 expression or activity, or deprivation of its primary substrate, glutamine, specifically suppressed ER stress induced by arsenite, but not tunicamycin. Induction of SNAT2 is coincident with the activation of the nutrient sensing mTOR pathway, which is at least partially required for arsenite-induced ER stress. Importantly, inhibition of the SNAT2 or the System L transporter, LAT1, suppressed mTOR activation by arsenite, supporting a role for these transporters in modulating amino acid signaling. These findings reveal SNAT2 as an important and specific mediator of arsenic-induced ER stress, and suggest a role for aberrant mTOR activation in arsenic-related human diseases. Furthermore, this study demonstrates the utility of RNAi screens in elucidating cellular mechanisms of environmental toxins. |
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Authors:
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Raymond S Oh; Wenchi Pan; Abdullah Yalcin; Hong Zhang; Tomas R Guilarte; Gokhan S Hotamisligil; David C Chrisitani; Quan Lu |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-3 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Harvard School of Public Health, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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