EIF2S1

Eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa, also known as EIF2S1, is a human gene.cite web | title = Entrez Gene: EIF2S1 eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1965| accessdate = ] cite journal | author = Ernst H, Duncan RF, Hershey JW | title = Cloning and sequencing of complementary DNAs encoding the alpha-subunit of translational initiation factor eIF-2. Characterization of the protein and its messenger RNA | journal = J. Biol. Chem. | volume = 262 | issue = 3 | pages = 1206–12 | year = 1987 | month = January | pmid = 2948954 | doi = | url = http://www.jbc.org/cgi/content/abstract/262/3/1206 | issn = ]

Function

The protein encoded by this gene is the alpha subunit of the translation initiation factor eIF2 complex which catalyzes the first regulated step of protein synthesis initiation, promoting the binding of the initiator tRNA to 40S ribosomal subunits. Binding occurs as a ternary complex of methionyl-tRNA, eIF2, and GTP. eIF2 is composed of 3 nonidentical subunits, alpha (36 kD, this article), beta (38 kD), and gamma (52 kD). The rate of formation of the ternary complex is modulated by the phosphorylation state of eIF2-alpha.

Clinical significance

After reperfusion following brain ischemia, there is inhibition of neuron protein synthesis due to phosphorylation of Eif2-alpha. There is colocalization between phosphorylated Eif2-alpha and cytosolic cytochrome c, which is released from mitochondria in apoptosis. Phosphorylated Eif2-alpha appeared before cytochrome c release, suggesting that phosphorylation of Eif2-alpha triggers cytochrome c release during apoptotic cell death.cite journal | author = Page AB, Owen CR, Kumar R, Miller JM, Rafols JA, White BC, DeGracia DJ, Krause GS | title = Persistent eIF2alpha(P) is colocalized with cytoplasmic cytochrome c in vulnerable hippocampal neurons after 4 hours of reperfusion following 10-minute complete brain ischemia | journal = Acta Neuropathol. | volume = 106 | issue = 1 | pages = 8–16 | year = 2003 | month = July | pmid = 12687390 | doi = 10.1007/s00401-003-0693-2 | url = | issn = ]

Mice heterozygous for the S51A mutation become obese and diabetic on a high-fat diet. Glucose intolerance resulted from reduced insulin secretion, defective transport of proinsulin, and a reduced number of insulin granules in beta cells. Hence proper functioning of EIF2S1 appears essential for preventing diet-induced type II diabetes. cite journal | author = Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, Ribick M, Schuit FC, Kaufman RJ | title = Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis | journal = Nat. Med. | volume = 11 | issue = 7 | pages = 757–64 | year = 2005 | month = July | pmid = 15980866 | doi = 10.1038/nm1259 | url = | issn = ]

Dephosphorylation inhibitors

Salubrinal is a selective inhibitor of enzymes that dephosphorylate EIF2-alpha.cite journal | author = Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J | title = A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress | journal = Science (journal) | volume = 307 | issue = 5711 | pages = 935–9 | year = 2005 | month = February | pmid = 15705855 | doi = 10.1126/science.1101902 | url = | issn = ] Salubrinal also blocks EIF2-alpha dephosphorylation by a herpes simplex virus protein and inhibits viral replication. EIF2-alpha phosphorylation is cytoprotective during endoplasmic reticulum stress.cite journal | author = Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D | title = Perk is essential for translational regulation and cell survival during the unfolded protein response | journal = Mol. Cell | volume = 5 | issue = 5 | pages = 897–904 | year = 2000 | month = May | pmid = 10882126 | doi = 10.1016/S1097-2765(00)80330-5 | url = | issn = ] cite journal | author = Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ | title = Translational control is required for the unfolded protein response and in vivo glucose homeostasis | journal = Mol. Cell | volume = 7 | issue = 6 | pages = 1165–76 | year = 2001 | month = June | pmid = 11430820 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/S1097-2765(01)00265-9 | issn = ]

ee also

* eIF2

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Hershey JW |title=Translational control in mammalian cells. |journal=Annu. Rev. Biochem. |volume=60 |issue= |pages= 717–55 |year= 1991 |pmid= 1883206 |doi= 10.1146/annurev.bi.60.070191.003441
*cite journal | author=Mao X, Green JM, Safer B, "et al." |title=Regulation of translation initiation factor gene expression during human T cell activation. |journal=J. Biol. Chem. |volume=267 |issue= 28 |pages= 20444–50 |year= 1992 |pmid= 1400363 |doi=
*cite journal | author=Mellor H, Proud CG |title=A synthetic peptide substrate for initiation factor-2 kinases. |journal=Biochem. Biophys. Res. Commun. |volume=178 |issue= 2 |pages= 430–7 |year= 1991 |pmid= 1677563 |doi=
*cite journal | author=Green SR, Spalding A, Ashford T, "et al." |title=Synthesis of human initiation factor-2 alpha in Saccharomyces cerevisiae. |journal=Gene |volume=108 |issue= 2 |pages= 253–8 |year= 1992 |pmid= 1748310 |doi=
*cite journal | author=Kramer G |title=Two phosphorylation sites on eIF-2 alpha. |journal=FEBS Lett. |volume=267 |issue= 2 |pages= 181–2 |year= 1990 |pmid= 2116318 |doi=
*cite journal | author=Ernst H, Duncan RF, Hershey JW |title=Cloning and sequencing of complementary DNAs encoding the alpha-subunit of translational initiation factor eIF-2. Characterization of the protein and its messenger RNA. |journal=J. Biol. Chem. |volume=262 |issue= 3 |pages= 1206–12 |year= 1987 |pmid= 2948954 |doi=
*cite journal | author=Kato S, Sekine S, Oh SW, "et al." |title=Construction of a human full-length cDNA bank. |journal=Gene |volume=150 |issue= 2 |pages= 243–50 |year= 1995 |pmid= 7821789 |doi=
*cite journal | author=Ray MK, Chakraborty A, Datta B, "et al." |title=Characteristics of the eukaryotic initiation factor 2 associated 67-kDa polypeptide. |journal=Biochemistry |volume=32 |issue= 19 |pages= 5151–9 |year= 1993 |pmid= 8098621 |doi=
*cite journal | author=Dever TE, Chen JJ, Barber GN, "et al." |title=Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 10 |pages= 4616–20 |year= 1993 |pmid= 8099443 |doi=
*cite journal | author=Barber GN, Wambach M, Wong ML, "et al." |title=Translational regulation by the interferon-induced double-stranded-RNA-activated 68-kDa protein kinase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 10 |pages= 4621–5 |year= 1993 |pmid= 8099444 |doi=
*cite journal | author=Miyamoto S, Chiorini JA, Urcelay E, Safer B |title=Regulation of gene expression for translation initiation factor eIF-2 alpha: importance of the 3' untranslated region. |journal=Biochem. J. |volume=315 ( Pt 3) |issue= |pages= 791–8 |year= 1996 |pmid= 8645159 |doi=
*cite journal | author=Yang W, Hinnebusch AG |title=Identification of a regulatory subcomplex in the guanine nucleotide exchange factor eIF2B that mediates inhibition by phosphorylated eIF2. |journal=Mol. Cell. Biol. |volume=16 |issue= 11 |pages= 6603–16 |year= 1996 |pmid= 8887689 |doi=
*cite journal | author=Brand SR, Kobayashi R, Mathews MB |title=The Tat protein of human immunodeficiency virus type 1 is a substrate and inhibitor of the interferon-induced, virally activated protein kinase, PKR. |journal=J. Biol. Chem. |volume=272 |issue= 13 |pages= 8388–95 |year= 1997 |pmid= 9079663 |doi=
*cite journal | author=Ting NS, Kao PN, Chan DW, "et al." |title=DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45. |journal=J. Biol. Chem. |volume=273 |issue= 4 |pages= 2136–45 |year= 1998 |pmid= 9442054 |doi=
*cite journal | author=Kimball SR, Heinzinger NK, Horetsky RL, Jefferson LS |title=Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B. |journal=J. Biol. Chem. |volume=273 |issue= 5 |pages= 3039–44 |year= 1998 |pmid= 9446619 |doi=
*cite journal | author=Shi Y, Vattem KM, Sood R, "et al." |title=Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. |journal=Mol. Cell. Biol. |volume=18 |issue= 12 |pages= 7499–509 |year= 1998 |pmid= 9819435 |doi=
*cite journal | author=Satoh S, Hijikata M, Handa H, Shimotohno K |title=Caspase-mediated cleavage of eukaryotic translation initiation factor subunit 2alpha. |journal=Biochem. J. |volume=342 ( Pt 1) |issue= |pages= 65–70 |year= 1999 |pmid= 10432301 |doi=
*cite journal | author=Berlanga JJ, Santoyo J, De Haro C |title=Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. |journal=Eur. J. Biochem. |volume=265 |issue= 2 |pages= 754–62 |year= 1999 |pmid= 10504407 |doi=
*cite journal | author=Lu J, O'Hara EB, Trieselmann BA, "et al." |title=The interferon-induced double-stranded RNA-activated protein kinase PKR will phosphorylate serine, threonine, or tyrosine at residue 51 in eukaryotic initiation factor 2alpha. |journal=J. Biol. Chem. |volume=274 |issue= 45 |pages= 32198–203 |year= 1999 |pmid= 10542257 |doi=

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