The eIF2A knockout mouse.
Eukaryotic initiation factor 2A (eIF2A) is a 65-kDa protein that was first identified in the early 1970s as a factor capable of stimulating initiator methionyl-tRNAi (Met-tRNAMeti) binding to 40S ribosomal subunits in vitro. However, in contrast to the eIF2, which stimulates Met-tRNAMetibinding to 40S ribosomal subunits in a GTP-dependent manner, eIF2A didn't reveal any GTP-dependence, but instead was found to direct binding of the Met-tRNAMetito 40S ribosomal subunits in a codon-dependent manner. eIF2A appears to be highly conserved across eukaryotic species, suggesting conservation of function in evolution. The yeast Saccharomyces cerevisae eIF2A null mutant revealed no apparent phenotype, however, it was found that in yeast eIF2A functions as a suppressor of internal ribosome entry site (IRES)-mediated translation. It was thus suggested that eIF2A my act by impinging on the expression of specific mRNAs. Subsequent studies in mammalian cell systems implicated eIF2A in non-canonical (non-AUG-dependent) translation initiation events involving near cognate UUG and CUG codons. Yet, the role of eIF2A in cellular functions remains largely enigmatic. As a first step toward characterization of the eIF2A function in mammalian systems in vivo, we have obtained homozygous eIF2A-total knockout (KO) mice, in which a gene trap cassette was inserted between eIF2A exons 1 and 2 disrupting expression of all exons downstream of the insertion. The KO mice strain is viable and to date displays no apparent phenotype. We believe that the eIF2A KO mice strain will serve as a valuable tool for researchers studying non-canonical initiation of translation in vivo.
a Texas A&M Institute for Genomic Medicine , College Station , TX , USA.
Andrei
A
Golovko
b Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University , Cleveland , OH , USA.
Artyom
A
Kojukhov
c Department of Genetics and Genome Sciences , Case Western Reserve University , Cleveland , OH , USA.
Bo-Jhih
BJ
Guan
a Texas A&M Institute for Genomic Medicine , College Station , TX , USA.
Benjamin
B
Morpurgo
d Department of Biochemistry , School of Medicine, Case Western Reserve University , Cleveland , OH , USA.
William C
WC
Merrick
b Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University , Cleveland , OH , USA.
Barsanjit
B
Mazumder
c Department of Genetics and Genome Sciences , Case Western Reserve University , Cleveland , OH , USA.
Maria
M
Hatzoglou
b Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University , Cleveland , OH , USA.|d Department of Biochemistry , School of Medicine, Case Western Reserve University , Cleveland , OH , USA.|e The Center for Gene Regulation in Health and Disease, Cleveland State University , Cleveland , OH , USA.
Anton A
AA
Komar
D000818:Animals; D001483:Base Sequence; D015852:Eukaryotic Initiation Factor-2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D015852:Eukaryotic Initiation Factor-2
alternative initiation pathways; eIF2A; initiation of translation; knockout mouse; non-AUG dependent initiation
EMBO J. 2008 Apr 9;27(7):1060-72
18337746
Annu Rev Biochem. 2014;83:779-812
24499181
Methods Enzymol. 1979;60:15-35
459896
Genes Dev. 2010 Aug 15;24(16):1787-801
20713520
Front Oncol. 2015 Jul 27;5:166
26284192
J Biol Chem. 2002 Oct 4;277(40):37079-87
12133843
Nat Struct Mol Biol. 2008 Aug;15(8):836-41
18604219
Nat Rev Mol Cell Biol. 2010 Feb;11(2):113-27
20094052
Methods Enzymol. 1979;60:35-52
459906
Elife. 2015 Jan 26;4:e03971
25621764
J Biol Chem. 2005 Apr 22;280(16):15601-11
15718232
Mol Cell. 2001 Jun;7(6):1165-76
11430820
Cell Mol Life Sci. 2013 Oct;70(19):3493-511
23354059
J Biol Chem. 2010 Aug 27;285(35):26779-87
20566627
Science. 2016 Jan 29;351(6272):aad3867
26823435
Science. 1998 Jun 12;280(5370):1757-60
9624054
J Biol Chem. 1975 Dec 10;250(23):9083-9
1194278
Science. 2012 Jun 29;336(6089):1719-23
22745432
J Struct Funct Genomics. 2014 Sep;15(3):125-30
24569939
Genes Dev. 2006 Jan 1;20(1):87-100
16391235
Biochem Soc Trans. 2016 Feb;44(1):273-8
26862215
Methods Enzymol. 1979;60:136-65
459895
EMBO J. 2011 May 10;30(12):2454-64
21556050
Genome Res. 2008 Oct;18(10):1670-9
18799693
J Biol Chem. 1975 Feb 25;250(4):1197-206
1112800
Cell Metab. 2014 May 6;19(5):836-48
24768297