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Hypoxia affects Slc7a5 expression through HIF‐2α in differentiated neuronal cells

An imbalance of branched‐chain amino acids (BCAAs) in the brain may result in neuropathological conditions, such as autism spectrum disorders. The L‐type amino acid transporter 1 (LAT1), encoded by the solute carrier transporter 7a5 (Slc7a5) gene, is critical for maintaining normal levels of BCAAs i...

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Autores principales: Onishi, Yuki, Hiraiwa, Manami, Kamada, Hikari, Iezaki, Takashi, Yamada, Takanori, Kaneda, Katsuyuki, Hinoi, Eiichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356171/
https://www.ncbi.nlm.nih.gov/pubmed/30761250
http://dx.doi.org/10.1002/2211-5463.12559
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author Onishi, Yuki
Hiraiwa, Manami
Kamada, Hikari
Iezaki, Takashi
Yamada, Takanori
Kaneda, Katsuyuki
Hinoi, Eiichi
author_facet Onishi, Yuki
Hiraiwa, Manami
Kamada, Hikari
Iezaki, Takashi
Yamada, Takanori
Kaneda, Katsuyuki
Hinoi, Eiichi
author_sort Onishi, Yuki
collection PubMed
description An imbalance of branched‐chain amino acids (BCAAs) in the brain may result in neuropathological conditions, such as autism spectrum disorders. The L‐type amino acid transporter 1 (LAT1), encoded by the solute carrier transporter 7a5 (Slc7a5) gene, is critical for maintaining normal levels of BCAAs in the brain. However, our understanding of the mechanisms that regulate the expression of LAT1/Slc7a5 in neurons is currently limited. Here, we demonstrate that hypoxic conditions result in upregulated expression of Slc7a5 in differentiated neuronal cells (Neuro2A cells induced to differentiate using all‐trans retinoic acid). Mechanistically, hypoxia‐induced expression of Slc7a5 is markedly reduced by short hairpin RNA (shRNA)‐mediated knockdown of hypoxia‐inducible factor 2α (HIF‐2α), but not by shRNA targeting HIF‐1α, in differentiated neuronal cells. Moreover, hypoxia increased the binding of HIF‐2α to the proximal promoter of Slc7a5 in differentiated neuronal cells. These results indicate that hypoxia directly enhances the recruitment of HIF‐2α to the proximal promoter of Slc7a5, resulting in its upregulated expression in differentiated neuronal cells. These findings indicate that Slc7a5 may be a novel gene responsive to hypoxia in a HIF‐2α‐dependent manner in differentiated neuronal cells.
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spelling pubmed-63561712019-02-13 Hypoxia affects Slc7a5 expression through HIF‐2α in differentiated neuronal cells Onishi, Yuki Hiraiwa, Manami Kamada, Hikari Iezaki, Takashi Yamada, Takanori Kaneda, Katsuyuki Hinoi, Eiichi FEBS Open Bio Research Articles An imbalance of branched‐chain amino acids (BCAAs) in the brain may result in neuropathological conditions, such as autism spectrum disorders. The L‐type amino acid transporter 1 (LAT1), encoded by the solute carrier transporter 7a5 (Slc7a5) gene, is critical for maintaining normal levels of BCAAs in the brain. However, our understanding of the mechanisms that regulate the expression of LAT1/Slc7a5 in neurons is currently limited. Here, we demonstrate that hypoxic conditions result in upregulated expression of Slc7a5 in differentiated neuronal cells (Neuro2A cells induced to differentiate using all‐trans retinoic acid). Mechanistically, hypoxia‐induced expression of Slc7a5 is markedly reduced by short hairpin RNA (shRNA)‐mediated knockdown of hypoxia‐inducible factor 2α (HIF‐2α), but not by shRNA targeting HIF‐1α, in differentiated neuronal cells. Moreover, hypoxia increased the binding of HIF‐2α to the proximal promoter of Slc7a5 in differentiated neuronal cells. These results indicate that hypoxia directly enhances the recruitment of HIF‐2α to the proximal promoter of Slc7a5, resulting in its upregulated expression in differentiated neuronal cells. These findings indicate that Slc7a5 may be a novel gene responsive to hypoxia in a HIF‐2α‐dependent manner in differentiated neuronal cells. John Wiley and Sons Inc. 2019-01-07 /pmc/articles/PMC6356171/ /pubmed/30761250 http://dx.doi.org/10.1002/2211-5463.12559 Text en © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Onishi, Yuki
Hiraiwa, Manami
Kamada, Hikari
Iezaki, Takashi
Yamada, Takanori
Kaneda, Katsuyuki
Hinoi, Eiichi
Hypoxia affects Slc7a5 expression through HIF‐2α in differentiated neuronal cells
title Hypoxia affects Slc7a5 expression through HIF‐2α in differentiated neuronal cells
title_full Hypoxia affects Slc7a5 expression through HIF‐2α in differentiated neuronal cells
title_fullStr Hypoxia affects Slc7a5 expression through HIF‐2α in differentiated neuronal cells
title_full_unstemmed Hypoxia affects Slc7a5 expression through HIF‐2α in differentiated neuronal cells
title_short Hypoxia affects Slc7a5 expression through HIF‐2α in differentiated neuronal cells
title_sort hypoxia affects slc7a5 expression through hif‐2α in differentiated neuronal cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356171/
https://www.ncbi.nlm.nih.gov/pubmed/30761250
http://dx.doi.org/10.1002/2211-5463.12559
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