The yeast eIF4E‐associated protein Eap1p attenuates <i>GCN4</i> translation upon TOR‐inactivation

Matsuo, Ryu; Konishi, Hiroyuki; Obata, Tohru; Kito, Keiji; Ota, Kazuhisa; Kitazono, Takanari; Ibayashi, Setsuro; Sasaki, Takuma; Iida, Mitsuo; Ito, Takashi

doi:10.1016/j.febslet.2005.03.043

Cited by 23 publications

(16 citation statements)

References 17 publications

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“…This later notion is supported by our binding experiments in which we found that under ER-stress conditions (where mTORC1 activation is reduced and P-eIF2α signaling is increased) Rheb losses it’s interaction with mTOR but remain bound to PERK (Figure 4G). As cell growth and ER stress is intimately connected (Tsang et al, 2010), such dynamic binding of Rheb may regulate normal physiology to reciprocally alter mTOR and P-eIF2α signaling, as observed in various cell types (Anand and Gruppuso, 2006; Deng et al, 2002; Hara et al, 1998; Kato et al, 2012; Kim et al, 2002; Koumenis et al, 2002; Kubota et al, 2003; Liu et al, 2006; Matsuo et al, 2005; Schneider et al, 2008; Tee and Proud, 2001). …”

Section: Discussionmentioning

confidence: 99%

“…Pharmacologic and genetic studies suggest that mTOR signaling does influence phospho-eIF2α. For instance, the mTOR inhibitor, rapamycin, is known to upregulate phospho-eIF2α in some cells (Anand and Gruppuso, 2006; Kato et al, 2012; Kubota et al, 2003; Matsuo et al, 2005). Similarly, heat inactivation of mTOR potentiates phospho-eIF2α in yeast cells, whereas the genetic deletion of PTEN, a negative regulator of mTOR, reduces phospho-eIF2α in cancerous cells (Mounir et al, 2009; Valbuena et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

et al. 2015

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SUMMARY Rheb, a ubiquitous small GTPase, is well known to bind and activate mTOR, which augments protein synthesis. Inhibition of protein synthesis is also physiologically regulated. Thus, with cell stress the unfolded protein response system leads to phosphorylation of the initiation factor eIF2α and arrest of protein synthesis. We now demonstrate a major role for Rheb in inhibiting protein synthesis through enhancing the phosphorylation of eIF2α by protein kinase-like endoplasmic reticulum kinase (PERK). Interplay between the stimulatory and inhibitory roles of Rheb may enable cells to modulate protein synthesis in response to varying environmental stresses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

et al. 2015

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“…In a related note, the yeast eIF4E-associated protein Eap1, which inhibits cap-dependent translation initiation via the TOR signaling cascade, attenuates induction of Gcn4 translation (48). Recent work has shown that overexpression of eIF4E-BP, the Eap1 functional equivalent in Drosophila , rescues Parkinsonian phenotypes in fly models of Parkinson disease by inhibiting cap-dependent translation and thereby inducing expression of genes involved in stress response (49).…”

Section: Discussionmentioning

confidence: 99%

Functional Gene Expression Profiling in Yeast Implicates Translational Dysfunction in Mutant Huntingtin Toxicity

Tauber

Miller-Fleming

Mason

et al. 2011

Journal of Biological Chemistry

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Huntington disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin (htt) protein. To uncover candidate therapeutic targets and networks involved in pathogenesis, we integrated gene expression profiling and functional genetic screening to identify genes critical for mutant htt toxicity in yeast. Using mRNA profiling, we have identified genes differentially expressed in wild-type yeast in response to mutant htt toxicity as well as in three toxicity suppressor strains: bna4Δ, mbf1Δ, and ume1Δ. BNA4 encodes the yeast homolog of kynurenine 3-monooxygenase, a promising drug target for HD. Intriguingly, despite playing diverse cellular roles, these three suppressors share common differentially expressed genes involved in stress response, translation elongation, and mitochondrial transport. We then systematically tested the ability of the differentially expressed genes to suppress mutant htt toxicity when overexpressed and have thereby identified 12 novel suppressors, including genes that play a role in stress response, Golgi to endosome transport, and rRNA processing. Integrating the mRNA profiling data and the genetic screening data, we have generated a robust network that shows enrichment in genes involved in rRNA processing and ribosome biogenesis. Strikingly, these observations implicate dysfunction of translation in the pathology of HD. Recent work has shown that regulation of translation is critical for life span extension in Drosophila and that manipulation of this process is protective in Parkinson disease models. In total, these observations suggest that pharmacological manipulation of translation may have therapeutic value in HD.

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“…Deregulating initiation by overexpression of the CAP-binding protein eIF4E leads to malignant transformation and therefore, not surprisingly, eIF4E is elevated in many human cancers (De Benedetti and Rhoads 1990;Lazaris-Karatzas et al 1990). In addition, TOR signaling and stress situations including membrane defects inhibit global initiation of translation by regulating binding of proteins (4E-BPs) to the initiation factor eIF4E (Cosentino et al 2000;Deloche et al 2004;Matsuo et al 2005;Ibrahimo et al 2006).…”

Section: Discussionmentioning

confidence: 99%

The SESA network links duplication of the yeast centrosome with the protein translation machinery

Sezen¹,

Seedorf²,

Schiebel³

2009

Genes Dev.

134

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The yeast spindle pole body (SPB), the functional equivalent of mammalian centrosome, duplicates in G1/S phase of the cell cycle and then becomes inserted into the nuclear envelope. Here we describe a link between SPB duplication and targeted translation control. When insertion of the newly formed SPB into the nuclear envelope fails, the SESA network comprising the GYF domain protein Smy2, the translation inhibitor Eap1, the mRNAbinding protein Scp160 and the Asc1 protein, specifically inhibits initiation of translation of POM34 mRNA that encodes an integral membrane protein of the nuclear pore complex, while having no impact on other mRNAs. In response to SESA, POM34 mRNA accumulates in the cytoplasm and is not targeted to the ER for cotranslational translocation of the protein. Reduced level of Pom34 is sufficient to restore viability of mutants with defects in SPB duplication. We suggest that the SESA network provides a mechanism by which cells can regulate the translation of specific mRNAs. This regulation is used to coordinate competing events in the nuclear envelope.[Keywords: Regulation of translation; spindle pole body; nuclear pore complex; Smy2; Eap1; Scp160] Supplemental material is available at http://www.genesdev.org.

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The yeast eIF4E‐associated protein Eap1p attenuates GCN4 translation upon TOR‐inactivation

Cited by 23 publications

References 17 publications

Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

Functional Gene Expression Profiling in Yeast Implicates Translational Dysfunction in Mutant Huntingtin Toxicity

The SESA network links duplication of the yeast centrosome with the protein translation machinery

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