Roles of activating transcription factor 4 in the murine response to asparaginase in liver.. Mus musculus

In liver, the anti-leukemic agent asparaginase (ASNase) increases phosphorylation of eukaryotic initiation factor 2 by general control nonderepressible 2 (GCN2) kinase. This event promotes gene-specific translation of activating transcription factor 4 (ATF4) which alters gene expression in response to amino acid depletion. The objective of this study was to investigate the role of GCN2 versus ATF4 in controlling the global transcriptome to ASNase in liver. We compared global gene expression patterns in livers from wildtype,Gcn2-/-, andAtf4-/-mice (all on C57BL/6J background) treated with ASNase or phosphate buffered saline (PBS) excipient. These analyses revealed that ATF4 controls a hepatic gene expression profile that partially overlaps with GCN2 both basally and following amino acid depletion by ASNase. Overall design: RNA-seq from liver of female and male mice treated with 8 daily intraperitoneal injections of asparaginase (3 international units per gram body weight) or equivolume excipient (phosphate buffered saline) in intact mice (WT), or mice with a homozygous deletion of Gcn2 (Gcn2-/-), or mice with a homozygous deletion of Atf4 (Atf4-/-). All mice were 8-12 weeks old and on the C57BL/6J genetic background for at least 8 generations. Three mice were used for each genotype and treatment (Total = 18 samples).