Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase

Abstract The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controllin...

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Autores principales:	Rana J. T. Al-Baghdadi, Inna A. Nikonorova, Emily T. Mirek, Yongping Wang, Jinhee Park, William J. Belden, Ronald C. Wek, Tracy G. Anthony
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8c386a86451643b7ab9901fa57812237
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spelling	oai:doaj.org-article:8c386a86451643b7ab9901fa578122372021-12-02T15:05:33ZRole of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase10.1038/s41598-017-01041-72045-2322https://doaj.org/article/8c386a86451643b7ab9901fa578122372017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01041-7https://doaj.org/toc/2045-2322Abstract The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controlling the hepatic transcriptome and mediating GCN2-mTORC1 signaling during asparaginase. We compared global gene expression patterns in livers from wildtype, Gcn2 −/−, and Atf4 −/− mice treated with asparaginase or excipient and further explored selected responses in livers from Atf4 +/− mice. Here, we show that ATF4 controls a hepatic gene expression profile that overlaps with GCN2 but is not required for downregulation of mTORC1 during asparaginase. Ingenuity pathway analysis indicates GCN2 independently influences inflammation-mediated hepatic processes whereas ATF4 uniquely associates with cholesterol metabolism and endoplasmic reticulum (ER) stress. Livers from Atf4 −/− or Atf4 +/− mice displayed an amplification of the amino acid response and ER stress response transcriptional signatures. In contrast, reduction in hepatic mTORC1 signaling was retained in Atf4 −/− mice treated with asparaginase. Conclusions: GCN2 and ATF4 serve complementary roles in the hepatic response to asparaginase. GCN2 functions to limit inflammation and mTORC1 signaling whereas ATF4 serves to limit the amino acid response and prevent ER stress during amino acid depletion by asparaginase.Rana J. T. Al-BaghdadiInna A. NikonorovaEmily T. MirekYongping WangJinhee ParkWilliam J. BeldenRonald C. WekTracy G. AnthonyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rana J. T. Al-Baghdadi Inna A. Nikonorova Emily T. Mirek Yongping Wang Jinhee Park William J. Belden Ronald C. Wek Tracy G. Anthony Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
description	Abstract The anti-leukemic agent asparaginase activates the integrated stress response (ISR) kinase GCN2 and inhibits signaling via mechanistic target of rapamycin complex 1 (mTORC1). The study objective was to investigate the protective role of activating transcription factor 4 (ATF4) in controlling the hepatic transcriptome and mediating GCN2-mTORC1 signaling during asparaginase. We compared global gene expression patterns in livers from wildtype, Gcn2 −/−, and Atf4 −/− mice treated with asparaginase or excipient and further explored selected responses in livers from Atf4 +/− mice. Here, we show that ATF4 controls a hepatic gene expression profile that overlaps with GCN2 but is not required for downregulation of mTORC1 during asparaginase. Ingenuity pathway analysis indicates GCN2 independently influences inflammation-mediated hepatic processes whereas ATF4 uniquely associates with cholesterol metabolism and endoplasmic reticulum (ER) stress. Livers from Atf4 −/− or Atf4 +/− mice displayed an amplification of the amino acid response and ER stress response transcriptional signatures. In contrast, reduction in hepatic mTORC1 signaling was retained in Atf4 −/− mice treated with asparaginase. Conclusions: GCN2 and ATF4 serve complementary roles in the hepatic response to asparaginase. GCN2 functions to limit inflammation and mTORC1 signaling whereas ATF4 serves to limit the amino acid response and prevent ER stress during amino acid depletion by asparaginase.
format	article
author	Rana J. T. Al-Baghdadi Inna A. Nikonorova Emily T. Mirek Yongping Wang Jinhee Park William J. Belden Ronald C. Wek Tracy G. Anthony
author_facet	Rana J. T. Al-Baghdadi Inna A. Nikonorova Emily T. Mirek Yongping Wang Jinhee Park William J. Belden Ronald C. Wek Tracy G. Anthony
author_sort	Rana J. T. Al-Baghdadi
title	Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
title_short	Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
title_full	Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
title_fullStr	Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
title_full_unstemmed	Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
title_sort	role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8c386a86451643b7ab9901fa57812237
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Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase

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