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Sci Rep. 2017 Apr 28;7(1):1272. doi: 10.1038/s41598-017-01041-7.

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

Author information

1
Endocrinology and Animal Biosciences Graduate Program, Rutgers, The State University of New Jersey, New Brunswick, NJ, 0890, USA.
2
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Al-Qadisiyah, Al-Qadisiayah, Iraq.
3
Department of Nutritional Sciences and the New Jersey Institute for Food, Nutrition and Health, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA.
4
Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, 0890, USA.
5
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
6
Department of Nutritional Sciences and the New Jersey Institute for Food, Nutrition and Health, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA. tracy.anthony@rutgers.edu.

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.

PMID:
28455513
PMCID:
PMC5430736
DOI:
10.1038/s41598-017-01041-7
[Indexed for MEDLINE]
Free PMC Article

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