- OMIM ID: 609280
- OMIM diseaseName:
- OMIM diseaseClinical_Synopsis:
- OMIM diseaseText:
EIF2AK4 belongs to a family of kinases that phosphorylate the alpha
subunit of eukaryotic translation initiation factor-2 (EIF2S1; 603907)
to downregulate protein synthesis in response to varied cellular
stresses (Berlanga et al., 1999).
Berlanga et al. (1999) cloned mouse Eif2ak4, which they designated Gcn2.
The deduced 1,648-amino acid protein has a calculated molecular mass of
186.4 kD. Gcn2 contains all 12 conserved catalytic subdomains of
eukaryotic serine/threonine protein kinases. The N-terminal half of Gcn2
contains a degenerate kinase domain, followed by a central catalytic
domain with a large insert typical of EIF2-alpha kinases. The C-terminal
half of Gcn2 contains 3 motifs conserved among class II aminoacyl-tRNA
synthetases (see 138295). Northern blot analysis detected Gcn2
expression in all mouse tissues examined, with highest levels in liver
and brain. Western blot analysis detected Gcn2 in mouse liver extracts
at an apparent molecular mass of about 190 kD.
By sequencing clones obtained from a size-fractionated fetal brain cDNA
library, Nagase et al. (2000) cloned EIF2AK4, which they designated
KIAA1338. The 3-prime UTR of the transcript contains an Alu element. The
deduced 1,495-amino acid protein shares significant similarity with S.
cerevisiae Gcn2. RT-PCR ELISA detected moderate to high EIF2AK4
expression in all tissues and specific brain regions examined. Highest
expression was detected in adult liver, ovary, and amygdala. Fetal liver
showed lower EIF2AK4 expression than adult liver.
Berlanga et al. (1999) demonstrated that Gcn2 immunopurified from mouse
liver extracts could phosphorylate rabbit Eif2 in vitro. Serum
starvation increased the level of phosphorylated EIF2-alpha more than
2-fold in human embryonic kidney cells transfected with mouse Eif2ak4.
Costa-Mattioli et al. (2005) reported a unique feature of hippocampal
slices from Gcn2-null mice: in CA1, a single 100-Hz train induced a
strong and sustained long-term potentiation (late LTP or L-LTP), which
was dependent on transcription and translation. In contrast, stimulation
that elicited L-LTP in wildtype slices, such as four 100-Hz trains or
forskolin, failed to evoke L-LTP in Gcn2-null slices. This aberrant
synaptic plasticity was mirrored in the behavior of Gcn2-null mice in
the Morris water maze: after weak training, their spatial memory was
enhanced, but it was impaired after more intense training. Activated
GCN2 stimulates mRNA translation of ATF4 (604064), an antagonist of cAMP
response element-binding protein (CREB; (123810)). Thus, in the
hippocampus of Gcn2-null mice, the expression of ATF4 was reduced and
CREB activity was increased. Costa-Mattioli et al. (2005) concluded that
their study provided genetic, physiologic, behavioral, and molecular
evidence that GCN2 regulates synaptic plasticity, as well as learning
and memory, through modulation of the ATF4/CREB pathway.
Hartz (2005) mapped the EIF2AK4 gene to chromosome 15q15.1 based on an
alignment of the EIF2AK4 sequence (GenBank GENBANK AB037759) with the
Zhang et al. (2002) found that Gcn2 -/- mice were viable and fertile and
exhibited no phenotypic abnormalities under standard growth conditions.
However, prenatal and neonatal mortality were 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. Cultured embryonic stem cells derived from
Gcn2 -/- mice failed to show the normal induction of Eif2-alpha
phosphorylation following leucine deprivation. Liver perfusion
experiments in wildtype mice showed that histidine limitation in the
presence of the histamine precursor histidinol induced a 2-fold increase
in Eif2-alpha phosphorylation and a concomitant reduction in Eif2b (see
606686). These responses were ablated in Gcn2 -/- livers.
Guo and Cavener (2007) found that lipid synthesis was repressed in the
livers of wildtype mice during prolonged leucine deprivation, whereas
lipid synthesis continued unabated in Gcn2 -/- mice, resulting in severe
liver steatosis. Failure to downregulate lipid synthesis resulted from
persistent expression of Srebp1c (SREBF1; 184756) and its downstream
transcriptional targets underlying fatty acid and triglyceride
- OMIM diseaseSee_Also:
- OMIM diseaseAllelic_Variants:
- OMIM diseaseCreation_Date: Patricia A. Hartz: 3/28/2005
- OMIM diseaseEdit_History_Data: wwang: 04/25/2007
- OMIM diseaseContributors: Patricia A. Hartz - updated: 04/25/2007
Ada Hamosh - updated: 10/10/2005
- OMIM diseaseReference: 1. Berlanga, J. J.; Santoyo, J.; de Haro, C.: Characterization of
a mammalian homolog of the GCN2 eukaryotic initiation factor 2-alpha
kinase. Europ. J. Biochem. 265: 754-762, 1999.
2. Costa-Mattioli, M.; Gobert, D.; Harding, H.; Herdy, B.; Azzi, M.;
Bruno, M.; Bidinosti, M.; Ben Mamou, C.; Marcinkiewicz, E.; Yoshida,
M.; Imataka, H.; Cuello, A. C.; Seidah, N.; Sossin, W.; Lacaille,
J.-C.; Ron, D.; Nader, K.; Sonenberg, N.: Translational control of
hippocampal synaptic plasticity and memory by the elF2-alpha kinase
GCN2. Nature 436: 1166-1170, 2005.
3. Guo, F.; Cavener, D. R.: The GCN2 eIF2-alpha kinase regulates
fatty-acid homeostasis in the liver during deprivation of an essential
amino acid. Cell Metab. 5: 103-114, 2007.
4. Hartz, P. A.: Personal Communication. Baltimore, Md. 3/28/2005.
5. Nagase, T.; Kikuno, R.; Ishikawa, K.; Hirosawa, M.; Ohara, O.:
Prediction of the coding sequences of unidentified human genes. XVI.
The complete sequences of 150 new cDNA clones from brain which code
for large proteins in vitro. DNA Res. 7: 65-73, 2000.
6. Zhang, P.; McGrath, B. C.; Reinert, J.; Olsen, D. S.; Lei, L.;
Gill, S.; Wek, S. A.; Vattem, K. M.; Wek, R. C.; Kimball, S. R.; Jefferson,
L. S.; Cavener, D. R.: The GCN2 eIF2-alpha kinase is required for
adaptation to amino acid deprivation in mice. Molec. Cell. Biol. 22: