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CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress

The cAMP response element binding protein (CREB) family activating transcription factor 1 (ATF1) and cAMP response element binding protein 1 (CREB1) have been reported in a diverse group of tumors, however, the mechanistic basis for this remains unclear. Here we found that CREB1 and ATF1 unexpectedl...

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Autores principales: Zhao, Lina, Xia, Wenjun, Jiang, Peng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223876/
https://www.ncbi.nlm.nih.gov/pubmed/34179023
http://dx.doi.org/10.3389/fcell.2021.698264
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author Zhao, Lina
Xia, Wenjun
Jiang, Peng
author_facet Zhao, Lina
Xia, Wenjun
Jiang, Peng
author_sort Zhao, Lina
collection PubMed
description The cAMP response element binding protein (CREB) family activating transcription factor 1 (ATF1) and cAMP response element binding protein 1 (CREB1) have been reported in a diverse group of tumors, however, the mechanistic basis for this remains unclear. Here we found that CREB1 and ATF1 unexpectedly regulate glutathione (GSH) biosynthesis by suppressing the expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutathione synthase (GSS), two key enzymes of GSH biosynthesis pathway. Mechanistic studies reveal that GCLM and GSS are direct transcriptional targets of CREB1 and ATF1. Through repressing the expression of these two enzymes, CREB1 and ATF1 reduce the GSH biosynthesis and the capability of cells to detoxicate reactive oxygen species (ROS), thereby increasing cellular susceptibility to oxidative stress. Therefore, our findings link CREB1 family to cellular metabolism, and uncover a potential therapeutic approach by targeting GCLM or oxidative stress for the treatment of tumors with relatively high expression of CREB1 family proteins.
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spelling pubmed-82238762021-06-25 CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress Zhao, Lina Xia, Wenjun Jiang, Peng Front Cell Dev Biol Cell and Developmental Biology The cAMP response element binding protein (CREB) family activating transcription factor 1 (ATF1) and cAMP response element binding protein 1 (CREB1) have been reported in a diverse group of tumors, however, the mechanistic basis for this remains unclear. Here we found that CREB1 and ATF1 unexpectedly regulate glutathione (GSH) biosynthesis by suppressing the expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutathione synthase (GSS), two key enzymes of GSH biosynthesis pathway. Mechanistic studies reveal that GCLM and GSS are direct transcriptional targets of CREB1 and ATF1. Through repressing the expression of these two enzymes, CREB1 and ATF1 reduce the GSH biosynthesis and the capability of cells to detoxicate reactive oxygen species (ROS), thereby increasing cellular susceptibility to oxidative stress. Therefore, our findings link CREB1 family to cellular metabolism, and uncover a potential therapeutic approach by targeting GCLM or oxidative stress for the treatment of tumors with relatively high expression of CREB1 family proteins. Frontiers Media S.A. 2021-06-10 /pmc/articles/PMC8223876/ /pubmed/34179023 http://dx.doi.org/10.3389/fcell.2021.698264 Text en Copyright © 2021 Zhao, Xia and Jiang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Zhao, Lina
Xia, Wenjun
Jiang, Peng
CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress
title CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress
title_full CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress
title_fullStr CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress
title_full_unstemmed CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress
title_short CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress
title_sort creb1 and atf1 negatively regulate glutathione biosynthesis sensitizing cells to oxidative stress
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223876/
https://www.ncbi.nlm.nih.gov/pubmed/34179023
http://dx.doi.org/10.3389/fcell.2021.698264
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