The Experts below are selected from a list of 17367 Experts worldwide ranked by ideXlab platform
Ronald C. Wek - One of the best experts on this subject based on the ideXlab platform.
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Eukaryotic Initiation Factor 2 Phosphorylation and Translational Control in Metabolism
Advances in nutrition (Bethesda Md.), 2012Co-Authors: Thomas D. Baird, Ronald C. WekAbstract:Regulation of mRNA translation is a rapid and effective means to couple changes in the cellular environment with global rates of protein synthesis. In response to stresses, such as nutrient deprivation and accumulation of misfolded proteins in the endoplasmic reticulum, phosphorylation of the α subunit of Eukaryotic Initiation Factor 2 (eIF2α~P) reduces general translation Initiation while facilitating the preferential translation of select transcripts, such as that encoding activating transcription Factor 4 (ATF4), a transcriptional activator of genes subject to the integrated stress response (ISR). In this review, we highlight the translational control processes regulated by nutritional stress, with an emphasis on the events triggered by eIF2α~P, and describe the family of Eukaryotic Initiation Factor 2 kinases and the mechanisms by which each sense different stresses. We then address 3 questions. First, what are the mechanisms by which eIF2α~P confers preferential translation on select mRNA and what are the consequences of the gene expression induced by the ISR? Second, what are the molecular processes by which certain stresses can differentially activate eIF2α~P and ATF4 expression? The third question we address is what are the modes of cross-regulation between the ISR and other stress response pathways, such as the unfolded protein response and mammalian target of rapamycin, and how do these regulatory schemes provide for gene expression programs that are tailored for specific stresses? This review highlights recent advances in each of these areas of research, emphasizing how eIF2α~P and the ISR can affect metabolic health and disease.
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Phosphorylation of Eukaryotic Initiation Factor-2α promotes the extracellular survival of obligate intracellular parasite Toxoplasma gondii
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Bradley R. Joyce, Ronald C. Wek, Sherry F. Queener, William J SullivanAbstract:While seeking a new host cell, obligate intracellular parasites, such as the protozoan Toxoplasma gondii, must be able to endure the stress of an extracellular environment. The mechanisms Toxoplasma use to remain viable while deprived of a host cell are not understood. We have previously shown that phosphorylation of Toxoplasma Eukaryotic Initiation Factor-2α (TgIF2α) is a conserved response to stress. Here we report the characterization of Toxoplasma harboring a point mutation (S71A) in TgIF2α that prevents phosphorylation. Results show that TgIF2α phosphorylation is critical for parasite viability because the TgIF2α-S71A mutants are ill-equipped to cope with life outside the host cell. The TgIF2α-S71A mutants also showed a significant delay in producing acute toxoplasmosis in vivo. We conclude that the phosphorylation of TgIF2α plays a crucial role during the lytic cycle by ameliorating the stress of the extracellular environment while the parasite searches for a new host cell.
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translation regulation by Eukaryotic Initiation Factor 2 kinases in the development of latent cysts in toxoplasma gondii
Journal of Biological Chemistry, 2008Co-Authors: Jana Narasimhan, Ronald C. Wek, Bradley R. Joyce, Arunasalam Naguleswaran, Aaron T Smith, Meredith R Livingston, Stacy E Dixon, Isabelle Coppens, William J SullivanAbstract:A key problem in the treatment of numerous pathogenic eukaryotes centers on their development into latent forms during stress. For example, the opportunistic protist Toxoplasma gondii converts to latent cysts (bradyzoites) responsible for recrudescence of disease. We report that Toxoplasma Eukaryotic Initiation Factor-2α (TgIF2α) is phosphorylated during stress and establish that protozoan parasites utilize translation control to modulate gene expression during development. Importantly, TgIF2α remains phosphorylated in bradyzoites, explaining how these cells maintain their quiescent state. Furthermore, we have characterized novel eIF2 kinases; one in the endoplasmic reticulum and a likely regulator of the unfolded protein response (TgIF2K-A) and another that is a probable responder to cytoplasmic stresses (TgIF2K-B). Significantly, our data suggest that 1) the regulation of protein translation through eIF2 kinases is associated with development, 2) eIF2α phosphorylation is employed by cells to maintain a latent state, and 3) endoplasmic reticulum and cytoplasmic stress responses evolved in Eukaryotic cells before the early diverging Apicomplexa. Given its importance to pathogenesis, eIF2 kinase-mediated stress responses may provide opportunities for novel therapeutics.
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the Eukaryotic Initiation Factor 2 kinase pathway facilitates differential gadd45a expression in response to environmental stress
Journal of Biological Chemistry, 2006Co-Authors: Hao Yuan Jiang, Li Jiang, Ronald C. WekAbstract:Phosphorylation of Eukaryotic Initiation Factor-2 (eIF2) regulates general and gene-specific translation in response to diverse environmental stresses. Central to gene expression induced by eIF2 phosphorylation is the preferential translation of ATF4, a basic zipper transcription activator. Phosphorylation of eIF2 and its attendant induction of ATF4 can lead to different patterns of gene expression depending on the environmental stress. This is of fundamental importance because eIF2 kinases can induce the expression of genes involved in survival as well as in apoptosis. In this report, we explore the molecular basis for why there can be differential expression of GADD45a, a stress-responsive protein that regulates genome stability, apoptosis, and immune responses. We find that whereas ATF4 is required for GADD45a transcription during many different environmental stresses, GADD45a protein accumulates only during a limited number of stress arrangements. The basis for this difference between measurable GADD45a mRNA and protein lies in the observation that GADD45a protein is labile. Those stress agents that enhance ATF4-directed GADD45a transcription and impede the turnover of GADD45a protein by blocking ubiquitin/proteasome-mediated degradation elevate GADD45a protein levels. By comparison, those stress arrangements that trigger ATF4 levels and GADD45a transcription, but do not perturb the proteasome pathway, only elevate GADD45a mRNA levels. This study highlights the molecular mechanisms by which environmental stresses can differentially control central regulatory proteins targeted by the eIF2 kinase pathway.
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parasite specific eif2 Eukaryotic Initiation Factor 2 kinase required for stress induced translation control
Biochemical Journal, 2004Co-Authors: William J Sullivan, Jana Narasimhan, Micah M Bhatti, Ronald C. WekAbstract:The ubiquitous intracellular parasite Toxoplasma gondii (phylum Apicomplexa) differentiates into an encysted form (bradyzoite) that can repeatedly re-emerge as a life-threatening acute infection (tachyzoite) upon impairment of immunity. Since the switch from tachyzoite to bradyzoite is a stress-induced response, we sought to identify components related to the phosphorylation of the alpha subunit of eIF2 (Eukaryotic Initiation Factor-2), a well-characterized event associated with stress remediation in other Eukaryotic systems. In addition to characterizing Toxoplasma eIF2alpha (TgIF2alpha), we have discovered a novel eIF2 protein kinase, designated TgIF2K-A (Toxoplasma gondii Initiation Factor-2kinase). Although the catalytic domain of TgIF2K-A contains sequence and structural features that are conserved among members of the eIF2 kinase family, TgIF2K-A has an extended N-terminal region that is highly divergent from other eIF2 kinases. TgIF2K-A specifically phosphorylates the regulatory serine residue of yeast eIF2alpha in vitro and in vivo, and can modulate translation when expressed in the yeast model system. We also demonstrate that TgIF2K-A phosphorylates the analogous regulatory serine residue of recombinant TgIF2alpha in vitro. Finally, we demonstrate that TgIF2alpha phosphorylation in tachyzoites is enhanced in response to heat shock or alkaline stress, conditions known to induce parasite differentiation in vitro. Collectively, this study suggests that eIF2 kinase-mediated stress responses are conserved in Apicomplexa, and a novel family member exists that may control parasite-specific events, including the clinically relevant conversion into bradyzoite cysts.
Donna M Driscoll - One of the best experts on this subject based on the ideXlab platform.
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Eukaryotic Initiation Factor 4a3 is a selenium regulated rna binding protein that selectively inhibits selenocysteine incorporation
Molecular Cell, 2009Co-Authors: Michael E Budiman, Jodi L Bubenik, Angela C Miniard, Lisa M Middleton, Carri A Gerber, Ayla Cash, Donna M DriscollAbstract:The synthesis of selenoproteins requires the translational recoding of the UGA stop codon as selenocysteine. During selenium deficiency, there is a hierarchy of selenoprotein expression, with certain selenoproteins synthesized at the expense of others. The mechanism by which the limiting selenocysteine incorporation machinery is preferentially utilized to maintain the expression of essential selenoproteins has not been elucidated. Here we demonstrate that Eukaryotic Initiation Factor 4a3 (eIF4a3) is involved in the translational control of a subset of selenoproteins. The interaction of eIF4a3 with the selenoprotein mRNA prevents the binding of SECIS binding protein 2, which is required for selenocysteine insertion, thereby inhibiting the synthesis of the selenoprotein. Furthermore, the expression of eIF4a3 is regulated in response to selenium. Based on knockdown and overexpression studies, eIF4a3 is necessary and sufficient to mediate selective translational repression in cells. Our results support a model in which eIF4a3 links selenium status with differential selenoprotein expression.
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Eukaryotic Initiation Factor 4a3 is a selenium regulated rna binding protein that selectively inhibits selenocysteine incorporation
Molecular Cell, 2009Co-Authors: Michael E Budiman, Jodi L Bubenik, Angela C Miniard, Lisa M Middleton, Carri A Gerber, Ayla Cash, Donna M DriscollAbstract:The synthesis of selenoproteins requires the translational recoding of the UGA stop codon as selenocysteine. During selenium deficiency, there is a hierarchy of selenoprotein expression, with certain selenoproteins synthesized at the expense of others. The mechanism by which the limiting selenocysteine incorporation machinery is preferentially utilized to maintain the expression of essential selenoproteins has not been elucidated. Here we demonstrate that Eukaryotic Initiation Factor 4a3 (eIF4a3) is involved in the translational control of a subset of selenoproteins. The interaction of eIF4a3 with the selenoprotein mRNA prevents the binding of SECIS binding protein 2, which is required for selenocysteine insertion, thereby inhibiting the synthesis of the selenoprotein. Furthermore, the expression of eIF4a3 is regulated in response to selenium. Based on knockdown and overexpression studies, eIF4a3 is necessary and sufficient to mediate selective translational repression in cells. Our results support a model in which eIF4a3 links selenium status with differential selenoprotein expression.
Christopher G Proud - One of the best experts on this subject based on the ideXlab platform.
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analysis of the regulatory motifs in Eukaryotic Initiation Factor 4e binding protein 1
FEBS Journal, 2008Co-Authors: Timothy M Healy, Bruno D Fonseca, Amanda Hayashi, Christopher G ProudAbstract:Mammalian target of rapamycin complex 1 (mTORC1) phosphorylates proteins such as Eukaryotic Initiation Factor 4E-binding protein 1 (4E-BP1) and the S6 kinases. These substrates contain short sequences, termed TOR signalling (TOS) motifs, which interact with the mTORC1 component raptor. Phosphorylation of 4E-BP1 requires an additional feature, termed the RAIP motif (Arg-Ala-Ile-Pro). We have analysed the interaction of 4E-BP1 with raptor and the amino acid residues required for functional RAIP and TOS motifs, as assessed by raptor binding and the phosphorylation of 4E-BP1 in human cells. Binding of 4E-BP1 to raptor strongly depends on an intact TOS motif, but the RAIP motif and additional C-terminal features of 4E-BP1 also contribute to this interaction. Mutational analysis of 4E-BP1 reveals that isoleucine is a key feature of the RAIP motif, that proline is also very important and that there is greater tolerance for substitution of the first two residues. Within the TOS motif, the first position (phenylalanine in the known motifs) is most critical, whereas a wider range of residues function in other positions (although an uncharged aliphatic residue is preferred at position three). These data provide important information on the structural requirements for efficient signalling downstream of mTORC1.
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regulation of cyclin d1 expression by mtorc1 signaling requires Eukaryotic Initiation Factor 4e binding protein 1
Oncogene, 2008Co-Authors: J Averous, Bruno D Fonseca, Christopher G ProudAbstract:Regulation of cyclin D1 expression by mTORC1 signaling requires Eukaryotic Initiation Factor 4E-binding protein 1
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structure of the Eukaryotic Initiation Factor eif 5 reveals a fold common to several translation Factors
Biochemistry, 2006Co-Authors: Maria R Conte, Geoff Kelly, Jeffrey J Babon, Domenico Sanfelice, James Youell, Stephen J Smerdon, Christopher G ProudAbstract:Eukaryotic Initiation Factor 5 (eIF5) plays multiple roles in translation Initiation. Its N-terminal domain functions as a GTPase-activator protein (GAP) for GTP bound to eIF2, while its C-terminal region nucleates the interactions between multiple translation Factors, including eIF1, which acts to inhibit GTP hydrolysis or P(i) release, and the beta subunit of eIF2. These proteins and the events in which they participate are critical for the accurate recognition of the correct start codon during translation Initiation. Here, we report the three-dimensional solution structure of the N-terminal domain of human eIF5, comprising two subdomains, both reminiscent of nucleic-acid-binding modules. The N-terminal subdomain contains the "arginine finger" motif that is essential for GAP function but which, unusually, resides in a partially disordered region of the molecule. This implies that a conformational reordering of this portion of eIF5 is likely to occur upon formation of a competent complex for GTP hydrolysis, following the appropriate activation signal. Interestingly, the N-terminal subdomain of eIF5 reveals an alpha/beta fold structurally similar to both the archaeal orthologue of the beta subunit of eIF2 and, unexpectedly, to eIF1. These results reveal a novel protein fold common to several Factors involved in related steps of translation Initiation. The implications of these observations are discussed in terms of the mechanism of translation Initiation.
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phosphorylation of Eukaryotic Initiation Factor 4e markedly reduces its affinity for capped mrna
Journal of Biological Chemistry, 2002Co-Authors: Gert C Scheper, Barbara Van Kollenburg, Yunjing Luo, Dixie J Goss, Christopher G ProudAbstract:In eukaryotes, a key step in the Initiation of translation is the binding of the Eukaryotic Initiation Factor 4E (eIF4E) to the cap structure of the mRNA. Subsequent recruitment of several components, including the small ribosomal subunit, is thought to allow migration of Initiation complexes and recognition of the Initiation codon. Mitogens and cytokines stimulate the phosphorylation of eIF4E at Ser209, but the functional consequences of this modification have remained a major unresolved question. Using fluorescence spectroscopy and surface plasmon resonance techniques, we show that phosphorylation of eIF4E markedly reduces its affinity for capped RNA, primarily due to an increased rate of dissociation. Variant eIF4E proteins harboring negatively charged acidic residues at position 209 also showed decreased binding to capped RNA. Furthermore, a basic residue at position 159 was shown to be essential for cap binding. Although eIF4E-binding protein 1 greatly stabilized binding of phosphorylated eIF4E to capped RNA, in the presence of eIF4E-binding protein 1 the phosphorylated form still dissociated faster compared with nonphopshorylated eIF4E. The implications of our findings for the mechanism of translation Initiation are discussed.
Nahum Sonenberg - One of the best experts on this subject based on the ideXlab platform.
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assessing Eukaryotic Initiation Factor 4f subunit essentiality by crispr induced gene ablation in the mouse
Cellular and Molecular Life Sciences, 2021Co-Authors: Patrick Senechal, Nahum Sonenberg, Regina Cencic, Francis Robert, Akiko Yanagiya, Jennifer Chu, Marilene Paquet, Jerry PelletierAbstract:Eukaryotic Initiation Factor (eIF) 4F plays a central role in the ribosome recruitment phase of cap-dependent translation. This heterotrimeric complex consists of a cap binding subunit (eIF4E), a DEAD-box RNA helicase (eIF4A), and a large bridging protein (eIF4G). In mammalian cells, there are two genes encoding eIF4A (eIF4A1 and eIF4A2) and eIF4G (eIF4G1 and eIF4G3) paralogs that can assemble into eIF4F complexes. To query the essential nature of the eIF4F subunits in normal development, we used CRISPR/Cas9 to generate mouse strains with targeted ablation of each gene encoding the different eIF4F subunits. We find that Eif4e, Eif4g1, and Eif4a1 are essential for viability in the mouse, whereas Eif4g3 and Eif4a2 are not. However, Eif4g3 and Eif4a2 do play essential roles in spermatogenesis. Crossing of these strains to the lymphoma-prone Eμ-Myc mouse model revealed that heterozygosity at the Eif4e or Eif4a1 loci significantly delayed tumor onset. Lastly, tumors derived from Eif4e∆38 fs/+/Eμ-Myc or Eif4a1∆5 fs/+/Eμ-Myc mice show increased sensitivity to the chemotherapeutic agent doxorubicin, in vivo. Our study reveals that eIF4A2 and eIF4G3 play non-essential roles in gene expression regulation during embryogenesis; whereas reductions in eIF4E or eIF4A1 levels are protective against tumor development in a murine Myc-driven lymphoma setting.
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granzyme b inhibits vaccinia virus production through proteolytic cleavage of Eukaryotic Initiation Factor 4 gamma 3
PLOS Pathogens, 2011Co-Authors: Marcelo Marcetpalacios, Nahum Sonenberg, Akiko Yanagiya, Brenda Duggan, Irene Shostak, Michele Barry, Tracy Geskes, John A Wilkins, Chris R BleackleyAbstract:Cytotoxic T lymphocytes (CTLs) are the major killer of virus-infected cells. Granzyme B (GrB) from CTLs induces apoptosis in target cells by cleavage and activation of substrates like caspase-3 and Bid. However, while undergoing apoptosis, cells are still capable of producing infectious viruses unless a mechanism exists to specifically inhibit viral production. Using proteomic approaches, we identified a novel GrB target that plays a major role in protein synthesis: Eukaryotic Initiation Factor 4 gamma 3 (eIF4G3). We hypothesized a novel role for GrB in translation of viral proteins by targeting eIF4G3, and showed that GrB cleaves eIF4G3 specifically at the IESD1408S sequence. Both GrB and human CTL treatment resulted in degradation of eIF4G3 and reduced rates of translation. When Jurkat cells infected with vaccinia virus were treated with GrB, there was a halt in viral protein synthesis and a decrease in production of infectious new virions. The GrB-induced inhibition of viral translation was independent of the activation of caspases, as inhibition of protein synthesis still occurred with addition of the pan-caspase inhibitor zVAD-fmk. This demonstrated for the first time that GrB prevents the production of infectious vaccinia virus by targeting the host translational machinery.
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Control of cell survival and proliferation by mammalian Eukaryotic Initiation Factor 4B.
Molecular and cellular biology, 2010Co-Authors: David Shahbazian, Yvan Martineau, Emmanuel Petroulakis, Armen Parsyan, Ivan Topisirovic, Bernard F. Gibbs, Yuri V. Svitkin, Nahum SonenbergAbstract:Translation Initiation plays an important role in cell growth, proliferation, and survival. The translation Initiation Factor eIF4B (Eukaryotic Initiation Factor 4B) stimulates the RNA helicase activity of eIF4A in unwinding secondary structures in the 5′ untranslated region (5′UTR) of the mRNA in vitro. Here, we studied the effects of eIF4B depletion in cells using RNA interference (RNAi). In agreement with the role of eIF4B in translation Initiation, its depletion resulted in inhibition of this step. Selective reduction of translation was observed for mRNAs harboring strong to moderate secondary structures in their 5′UTRs. These mRNAs encode proteins, which function in cell proliferation (Cdc25C, c-myc, and ODC [ornithine decarboxylase]) and survival (Bcl-2 and XIAP [X-linked inhibitor of apoptosis]). Furthermore, eIF4B silencing led to decreased proliferation rates, promoted caspase-dependent apoptosis, and further sensitized cells to camptothecin-induced cell death. These results demonstrate that eIF4B is required for cell proliferation and survival by regulating the translation of proliferative and prosurvival mRNAs.
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elevated levels of cyclin d1 protein in response to increased expression of Eukaryotic Initiation Factor 4e
Molecular and Cellular Biology, 1993Co-Authors: Igor B Rosenwald, A Lazariskaratzas, Nahum Sonenberg, Emmett V SchmidtAbstract:Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors. Recent studies suggested that high protein levels of cyclin D1 are not always produced when cyclin D1 mRNA is overexpressed in transfected cells, suggesting that posttranscriptional events may be important in cyclin D1 regulation. The mRNA cap-binding protein (Eukaryotic Initiation Factor 4E [eIF-4E]) is a potential regulatory of several posttranscriptional events, and it can itself induce neoplastic transformation. Consequently, we examined eIF-4E as a potential regulator of cyclin D1. Overexpression of cyclin D1 mRNA in NIH 3T3 cells did not increase cyclin D1 protein. In contrast, overexpression of eIF-4E markedly increased the amount of cyclin D1 protein in NIH 3T3 cells. This increase was specific to cyclin D1 in comparison with the retinoblastoma gene product, c-Myc, actin, and Eukaryotic Initiation Factor 2 alpha. We also examined cyclin D1 protein in cells expressing an estrogen receptor-Myc fusion protein because we previously found that eIF-4E increases after induction of c-myc function. In these cells, increased levels of eIF-4E protein were closely followed by increases in levels of cyclin D1 protein, but the level of cyclin D1 mRNA was not increased. We conclude that increases in cyclin D1 levels may result from increased expression of eIF-4E, and this regulation may be one determinant of cyclin D1 levels in the cell.
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the p46 subunit of Eukaryotic Initiation Factor eif 4f exchanges with eif 4a
Journal of Biological Chemistry, 1993Co-Authors: Jane Yoderhill, Nahum Sonenberg, Arnim Pause, William C. MerrickAbstract:Abstract The p46 subunit of Eukaryotic Initiation Factor (eIF)-4F purified from rabbit reticulocyte lysate has previously been found to be composed of eIF-4AI and eIF-4AII in a 4:1 ratio, respectively, whereas the free form of rabbit eIF-4A is composed solely of eIF-4AI. Using sucrose gradient centrifugation and an m7GTP-Sepharose 4B assay, it was shown that eIF-4A exchanges with the p46 subunit of eIF-4F. Incubation of [14C]eIF-4A and eIF-4F resulted in the incorporation of [14C] eIF-4A into the eIF-4F complex. Conversely, the [14C] p46 subunit of [14C]eIF-4F was shown to dissociate from the [14C]eIF-4F complex in the presence of eIF-4A, presumably due to the incorporation of unlabeled eIF-4A. Similar experiments were conducted in which 14C-labeled Initiation Factors were incubated with rabbit reticulocyte lysate. When [14C]eIF-4A was incubated with lysate, [14C]eIF-4A became incorporated into the eIF-4F complex present in the lysate. Additionally, when [14C]eIF-4F was incubated with lysate, the [14C]p46 subunit of [14C]eIF-4F dissociated from the [14C]eIF-4F complex, most likely due to the exchange of unlabeled eIF-4A (present in the lysate) with the [14C]p46 subunit. The exchange of mouse eIF-4AI and eIF-4AII expressed in Escherichia coli was also investigated in the presence of eIF-4F and rabbit reticulocyte lysate. Both the sucrose gradient experiments and m7GTP-Sepharose 4B assays demonstrated that the [14C]p46 subunit of [14C]eIF-4F was displaced in the presence of eIF-4AI or eIF-4AII and that mouse [14C]eIF-4AI or [14C]eIF-4AII became incorporated into the eIF-4F complex in the same manner as rabbit reticulocyte eIF-4A.
Jerry Pelletier - One of the best experts on this subject based on the ideXlab platform.
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assessing Eukaryotic Initiation Factor 4f subunit essentiality by crispr induced gene ablation in the mouse
Cellular and Molecular Life Sciences, 2021Co-Authors: Patrick Senechal, Nahum Sonenberg, Regina Cencic, Francis Robert, Akiko Yanagiya, Jennifer Chu, Marilene Paquet, Jerry PelletierAbstract:Eukaryotic Initiation Factor (eIF) 4F plays a central role in the ribosome recruitment phase of cap-dependent translation. This heterotrimeric complex consists of a cap binding subunit (eIF4E), a DEAD-box RNA helicase (eIF4A), and a large bridging protein (eIF4G). In mammalian cells, there are two genes encoding eIF4A (eIF4A1 and eIF4A2) and eIF4G (eIF4G1 and eIF4G3) paralogs that can assemble into eIF4F complexes. To query the essential nature of the eIF4F subunits in normal development, we used CRISPR/Cas9 to generate mouse strains with targeted ablation of each gene encoding the different eIF4F subunits. We find that Eif4e, Eif4g1, and Eif4a1 are essential for viability in the mouse, whereas Eif4g3 and Eif4a2 are not. However, Eif4g3 and Eif4a2 do play essential roles in spermatogenesis. Crossing of these strains to the lymphoma-prone Eμ-Myc mouse model revealed that heterozygosity at the Eif4e or Eif4a1 loci significantly delayed tumor onset. Lastly, tumors derived from Eif4e∆38 fs/+/Eμ-Myc or Eif4a1∆5 fs/+/Eμ-Myc mice show increased sensitivity to the chemotherapeutic agent doxorubicin, in vivo. Our study reveals that eIF4A2 and eIF4G3 play non-essential roles in gene expression regulation during embryogenesis; whereas reductions in eIF4E or eIF4A1 levels are protective against tumor development in a murine Myc-driven lymphoma setting.
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selective targeting of the dead box rna helicase Eukaryotic Initiation Factor eif 4a by natural products
Natural Product Reports, 2020Co-Authors: Leo Shen, Jerry PelletierAbstract:Covering: up to 2019Pharmacological targeting of Eukaryotic mRNA translation Initiation is a promising approach for cancer therapy, since several signaling pathways that are commonly deregulated during tumor progression converge on this process. The DEAD-box helicase, Eukaryotic Initiation Factor (eIF) 4A, is essential for translation Initiation and facilitates the loading of the 43S pre-Initiation complex onto mRNAs. Hippuristanol, rocaglates, and pateamine A are natural products that each target eIF4A by interfering with the helicase's RNA-binding activity in distinct manners. They exert a selective change in gene expression that results in potent anti-tumorigenic activity in pre-clinical studies. This review will provide an update on the molecular mechanisms of action of these natural products.
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hippuristanol a potent steroid inhibitor of Eukaryotic Initiation Factor 4a
Translation (Austin Tex.), 2016Co-Authors: Regina Cencic, Jerry PelletierAbstract:Protein synthesis and its regulatory signaling pathways play essential roles in the Initiation and maintenance of the cancer phenotype. Insight obtained over the last 3 decades on the mechanisms regulating translation in normal and transformed cells have revealed that perturbed control in cancer cells may offer an Achilles' heel for the development of novel anti-neoplastic agents. Several small molecule inhibitors have been identified and characterized that target translation Initiation - more specifically, the rate-limiting step where ribosomes are recruited to mRNA templates. Among these, hippuristanol, a polyhydroxysteroid from the gorgonian Isis hippuris has been found to inhibit translation Initiation by blocking the activity of Eukaryotic Initiation Factor (eIF) 4A, an essential RNA helicase involved in this process. Herein, we highlight the biological properties of this compound, its potential development as an anti-cancer agent, and its use to validate eIF4A as an anti-neoplastic target.
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regulation of Eukaryotic Initiation Factor 4aii by myod during murine myogenic cell differentiation
PLOS ONE, 2014Co-Authors: Gabriela Galiciavazquez, Sergio Di Marco, Xian J Lian, Jennifer F, Imed Gallouzi, Jerry PelletierAbstract:Gene expression during muscle cell differentiation is tightly regulated at multiple levels, including translation Initiation. The PI3K/mTOR signalling pathway exerts control over protein synthesis by regulating assembly of Eukaryotic Initiation Factor (eIF) 4F, a heterotrimeric complex that stimulates recruitment of ribosomes to mRNA templates. One of the subunits of eIF4F, eIF4A, supplies essential helicase function during this phase of translation. The presence of two cellular eIF4A isoforms, eIF4AI and eIF4AII, has long thought to impart equivalent functions to eIF4F. However, recent experiments have alluded to distinct activities between them. Herein, we characterize distinct regulatory mechanisms between the eIF4A isoforms during muscle cell differentiation. We find that eIF4AI levels decrease during differentiation whereas eIF4AII levels increase during myofiber formation in a MyoD-dependent manner. This study characterizes a previously undefined mechanism for eIF4AII regulation in differentiation and highlights functional differences between eIF4AI and eIF4AII. Finally, RNAi-mediated alterations in eIF4AI and eIF4AII levels indicate that the myogenic process can tolerate short term reductions in eIF4AI or eIF4AII levels, but not both.