TY - JOUR
T1 - The GCN2 eIF2α kinase is required for adaptation to amino acid deprivation in mice
AU - Zhang, Peichuan
AU - McGrath, Barbara C.
AU - Reinert, Jamie
AU - Olsen, De Anne S.
AU - Lei, Li
AU - Gill, Sangeeta
AU - Wek, Sheree A.
AU - Vattem, Krishna M.
AU - Wek, Ronald C.
AU - Kimball, Scot R.
AU - Jefferson, Leonard S.
AU - Cavener, Douglas R.
PY - 2002/10
Y1 - 2002/10
N2 - The GCN2 eIF2α 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 eIF2α 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 eIF2α and a concomitant reduction in eIF2B activity in perfused livers from wild-type mice, but no changes in livers from Gcn2-/- mice.
AB - The GCN2 eIF2α 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 eIF2α 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 eIF2α and a concomitant reduction in eIF2B activity in perfused livers from wild-type mice, but no changes in livers from Gcn2-/- mice.
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U2 - 10.1128/MCB.22.19.6681-6688.2002
DO - 10.1128/MCB.22.19.6681-6688.2002
M3 - Article
C2 - 12215525
AN - SCOPUS:0036771638
SN - 0270-7306
VL - 22
SP - 6681
EP - 6688
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 19
ER -