General Control Nonderepressible 2 and ATF4 Direct Liver Genes during Asparaginase Treatment in Mice

  • Rana Jaber Tarish Department of Physiology, College of Veterinary Medicine, University of Al-Qadisiyah, Iraq

Abstract

Asparaginase (ASNase) treatment results in synthesis of some factors such as ATF4. The eIF2-ATF4 pathway is essential for cell survival during amino acid starvation conditions. Activation of the AAR in liver requires the eIF2 kinase called general control nonderepressible 2 kinase (GCN2). To what extent activation of the GCN2-eIF2-AAR is mediated by ATF4 is unknown. Our objective and hypothesis are addressed in our aim to describe the liver response to ASNase in mice deleted for Atf4. RNA sequencing alongside complementary biochemical approaches were performed in the livers of mice treated with eight daily injections of ASNase or saline excipient. Cellular pathways examined in detail included the AAR. We discovered that global hepatic gene expression patterns in Atf4 knockout mice overlapped with Gcn2 knockout mice. Shared hepatic pathways or processes altered during ASNase included mTOR signaling, and xenobiotic metabolism. On the other hand, loss of Atf4 during ASNase uniquely altered gene expression signatures reflecting signaling via eIF2 and ER stress. This research provides insight into the importance of genetic background of patients in choosing ASNase as a treatment

References

1-Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. (2006); Jan 12; 354:166-78.
2-Landau H, Lamanna N. Clinical manifestations and treatment of newly diagnosed acute lymphoblastic leukemia in adults. Curr Hematol Malig Rep. (2006); Sep; 1(3):171-9. doi: 10.1007/s11899-996-0005-8.
3-Appel IM, Hop WC, van Kessel-Bakvis C, Stigter R, Pieters R. L-ASNase and the effect of age on coagulation and fibrinolysis in childhood acute lymphoblastic leukemia. Thromb Haemost. (2008); Aug; 100:330-7.
4-Reinert RB, Oberle LM, Wek SA, Bunpo P, Wang XP, Mileva I, Goodwin LO, Aldrich CJ, Durden DL, McNurlan MA, Wek RC, Anthony TG. Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-ASNase. J Biol Chem. (2006); Oct 20; 281(42):31222-33. Epub 2006 Aug 24.
5-Bunpo P, Dudley A, Cundiff JK, Cavener DR, Wek RC, Anthony TG. GCN2 protein kinase is required to activate amino acid deprivation responses in mice treated with the anti-cancer agent L-ASNase. J Biol Chem. (2009); Nov 20; 284(47):32742-9
6-Kilberg MS, Shan J, Su N. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab. (2009); Nov; 20(9):436-43.
Published
2018-12-30