The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice.

Zhang P, McGrath BC, Reinert J, Olsen DS, Lei L, Gill S, Wek SA, Vattem KM, Wek RC, Kimball SR, Jefferson LS, Cavener DR
Mol Cell Biol. 2002 22 (19): 6681-8

PMID: 12215525 · PMCID: PMC134046 · DOI:10.1128/mcb.22.19.6681-6688.2002

The GCN2 eIF2alpha kinase is essential for activation of the general amino acid control pathway in yeast when one or more amino acids become limiting for growth. GCN2's function in mammals is unknown, but must differ, since mammals, unlike yeast, can synthesize only half of the standard 20 amino acids. To investigate the function of mammalian GCN2, we have generated a Gcn2(-/-) knockout strain of mice. Gcn2(-/-) mice are viable, fertile, and exhibit no phenotypic abnormalities under standard growth conditions. However, prenatal and neonatal mortalities are significantly increased in Gcn2(-/-) mice whose mothers were reared on leucine-, tryptophan-, or glycine-deficient diets during gestation. Leucine deprivation produced the most pronounced effect, with a 63% reduction in the expected number of viable neonatal mice. Cultured embryonic stem cells derived from Gcn2(-/-) mice failed to show the normal induction of eIF2alpha phosphorylation in cells deprived of leucine. To assess the biochemical effects of the loss of GCN2 in the whole animal, liver perfusion experiments were conducted. Histidine limitation in the presence of histidinol induced a twofold increase in the phosphorylation of eIF2alpha and a concomitant reduction in eIF2B activity in perfused livers from wild-type mice, but no changes in livers from Gcn2(-/-) mice.

MeSH Terms (26)

Adaptation, Physiological Animals Animals, Newborn Cells, Cultured Eukaryotic Initiation Factor-2 Eukaryotic Initiation Factor-2B Female Fetal Viability Food, Formulated Gene Expression Regulation Gene Targeting Glycine Heterozygote Homozygote Leucine Liver Mice Mice, Knockout Phosphorylation Pregnancy Prenatal Exposure Delayed Effects Protein-Serine-Threonine Kinases Protein Kinases Protein Subunits Stem Cells Tryptophan

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