Tomek W, et al 2002 reported the regulation of translation during in vitro maturation of bovine
oocytes and the role of MAP kinase, eIF4E (cap binding protein)
phosphorylation, and eIF4E-BP1.
Meiotic maturation of mammalian oocytes (transition from prophase I to
metaphase II) is accompanied by complex changes in the protein phosphorylation
pattern. At least two major protein kinases are involved in these events;
namely, cdc2 kinase and mitogen-activated protein (MAP) kinase, because the
inhibition of these kinases arrest mammalian oocytes in the germinal vesicle
(GV) stage. The authors show that during meiotic maturation of bovine oocytes, the
translation initiation factor, eIF4E (the cap binding protein), gradually
becomes phosphorylated. This substantial phosphorylation begins at the time of
germinal vesicle breakdown (GVBD and continues to the metaphase II stage. The
onset of eIF4E phosphorylation occurs in parallel with a significant increase
in overall protein synthesis. However, although eIF4E is nearly fully
phosphorylated in metaphase II oocytes, protein synthesis reaches only basal
levels at this stage, similar to that of prophase I oocytes, in which the
factor remains unphosphorylated. A specific repressor
of eIF4E, the binding protein 4E-BP1, is present and could be involved in
preventing eIF4E function in metaphase 11 stage oocytes. Recently, two protein
kinases, called Mnk1 and Mnk2, have been identified in somatic cells as eIF4E
kinases, both of which are substrates of MAP kinase in vivo. In bovine
oocytes, a specific inhibitor of cdk kinases, butyrolactone I, arrests oocytes
in GV stage and prevents activation of both cdc2 and MAP kinase. Under these
conditions, the phosphorylation of eIF4E is also blocked, and its function in
initiation of translation is impaired. In contrast, PD 098059, a specific
inhibitor of the MAP kinase activation pathway, which inhibits the MAP kinase
kinase, called MEK function, leads only to a postponed GVBD, and a delay in
MAP kinase and eIF4E phosphorylation. These results indicate that in bovine
oocytes, 1) MAP kinase activation is only partially dependent on MEK kinase,
2) MAP kinase is involved in eIF4E phosphorylation, and 3) the abundance of
fully phosphorylated eIF4E does not necessarily directly stimulate protein
synthesis. A possible MEK kinase-independent pathway of MAP kinase
phosphorylation and the role of 4E-BP1 in repressing translation in metaphase
II oocytes are discussed.
NCBI Summary:
The protein encoded by this gene is a component of the eukaryotic translation initiation factor 4F complex, which recognizes the 7-methylguanosine cap structure at the 5' end of messenger RNAs. The encoded protein aids in translation initiation by recruiting ribosomes to the 5'-cap structure. Association of this protein with the 4F complex is the rate-limiting step in translation initiation. This gene acts as a proto-oncogene, and its expression and activation is associated with transformation and tumorigenesis. Several pseudogenes of this gene are found on other chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]
General function
Apoptosis, Translation factor
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Oogenesis, Oocyte maturation, Early embryo development
Comment
Clast4, the murine homologue of human eIF4E-Transporter, is highly expressed in developing oocytes and post-translationally modified at meiotic maturation Villaescusa JC, et al .
In metazoans, translational regulation of a set of maternal mRNAs directs oocyte maturation and early embryogenesis. These transcripts are often kept dormant until their products are spatially and temporally required in development. The interaction between general translation factors (i.e. eIF4E) and their specific interactors influences translation initiation. A search of the protein database for a mouse homologue of the Drosophila Cup protein, a translational repressor during female germ-line development, identified the product of the Clast4 gene. In this report, we show that Clast4 mRNA and protein are highly expressed within the cytoplasm of growing oocytes. The Clast4 protein is stable during this developmental window and post-translationally modified by phosphorylation upon oocyte meiotic maturation. Additionally, we show that Clast4 and eIF4E directly interact by means of a canonical and functional eIF4E-binding motif. Our results suggest that Clast4, similar to Drosophila Cup, may act at the translational level during murine female germ-line development.
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
CPEB interacts with an ovary-specific eIF4E and 4E-T in early Xenopus oocytes. Minshall N et al. CPEB (cytoplasmic polyadenylation element-binding protein) is an important regulator of translation in oocytes and neurons. Although previous studies of CPEB in late Xenopus oocytes involve the eIF4E-binding protein maskin as the key factor for the repression of maternal mRNA, a second mechanism must exist as maskin is absent earlier in oogenesis. Using co-immunoprecipitation and gel filtration assays we show that CPEB specifically interacts, via protein:protein interactions, with the RNA helicase Xp54, the RNA-binding proteins P100(Pat1) and RAP55B, the eIF4E-binding protein 4E-T and an eIF4E protein. Remarkably, these CPEB complex proteins, have been characterized, in one or more organism, as P-body, maternal or neuronal granule components. We do not detect interactions with eIF4E1a, the canonical cap-binding factor, eIF4G or eIF4A nor with proteins expressed late in oogenesis including maskin, PARN and 4E-BP1. The eIF4E protein was identified as eIF4E1b, a close homolog of eIF4E1a, whose expression is restricted to oocytes and early embryos. Though eIF4E1b possesses all residues required for cap- and eIF4G-binding, it binds m7GTP weakly, and in pull-down assays, rather than binding eIF4G, binds 4E-T, in a manner independent of the consensus eIF4E-binding site, YSKEELL. Wild type and Y-A mutant 4E-T (which binds eIF4E1b but not eIF4E1a), when tethered to a reporter mRNA represses its translation in a cap-dependent manner and injection of eIF4E1b antibody accelerates meiotic maturation. Altogether our data suggest that CPEB, partnered with several highly conserved RNA-binding partners, inhibits protein synthesis in oocytes using a novel pairing of 4E-T and eIF4E1b.
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: embryonic lethal Comment: The regulation of the mammalian maternal-to-embryonic transition by eukaryotic translation initiation factor 4E. Li Y et al. (2021) Eukaryotic translation initiation factor 4E (eIF4E) mediates CAP-dependent translation. Genetic and inhibitor studies show its expression was required for the successful transition from maternal to embryonic control of mouse embryo development. eIF4E was in the oocyte and in the cytoplasm soon after fertilization, and at each stage of early development. Functional knockout (Eif4e-/-) by PiggyBac (PB) [Act-RFP] transposition caused peri-implantation embryonic lethality due to the failure of normal epiblast formation. Maternal stores of eIF4E supported development up to the 2-4-cell stage after which new expression occurred from both alleles. Inhibition of the maternally acquired stores of eIF4E (4EGI-1 inhibitor) resulted in a block at the 2-cell stage. eIF4E activity was required for new protein synthesis in the 2-cell embryo and knockout embryos had lower translational activity than wildtype embryos. 4E-BP1 is a hypophosphorylation-dependent negative regulator of eIF4E. mTOR activity was required for 4E-BP1 phosphorylation and inhibiting mTOR retarded embryo development. This study shows that eIF4E activity is regulated at key embryonic transitions in the mammalian embryo and is essential for the successful transition to embryonic control of development.//////////////////