Al-Baghdadi, Rana J. T.Nikonorova, Inna A.Mirek, Emily T.Wang, YongpingPark, JinheeBelden, William J.Wek, Ronald C.Anthony, Tracy G.2017-08-242017-08-242017-04-28Al-Baghdadi, R. J. T., Nikonorova, I. A., Mirek, E. T., Wang, Y., Park, J., Belden, W. J., … Anthony, T. G. (2017). Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase. Scientific Reports, 7, 1272. http://doi.org/10.1038/s41598-017-01041-7https://hdl.handle.net/1805/13911The 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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesAnti-leukemic agentsAsparaginaseIntegrated stress responseKinase GCN2Activating transcription factor 4 (ATF4)Article