A novel shuttling protein, 4E-T, mediates the nuclear import of the mRNA 5' cap-binding protein, eIF4E

Dostie, Josée; Ferraiuolo, Maria; Pause, Arnim; Adam, Stephen A.; Sonenberg, Nahum

doi:10.1093/emboj/19.12.3142

Cited by 180 publications

(215 citation statements)

References 80 publications

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“…eIF4E can mediate nuclear export of the cyclin D1 mRNA (Rousseau et al, 1996). Entry of eIF4E into the nucleus appears to be mediated by 4E-T (Dostie et al, 2000), which contains a similar eIF4E-binding motif to that in 4E-BP1. Therefore, binding of 4E-BP1 to eIF4E could prevent eIF4E entering the nucleus, potentially affecting the transport of the cyclin D1 mRNA into the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

2007

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There is currently substantial interest in the regulation of cell function by mammalian target of rapamycin (mTOR), especially effects linked to the rapamycin-sensitive mTOR complex 1 (mTORC1). Rapamycin induces G 1 arrest and blocks proliferation of many tumor cells, suggesting that the inhibition of mTORC1 signaling may be useful in cancer therapy. In MCF7 breast adenocarcinoma cells, rapamycin decreases levels of cyclin D1, without affecting cytoplasmic levels of its mRNA. In some cell-types, rapamycin does not affect cyclin D1 levels, whereas the starvation for leucine (which impairs mTORC1 signaling more profoundly than rapamycin) does. This pattern correlates with the behavior of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1, an mTORC1 target that regulates translation initiation). siRNA-mediated knockdown of 4E-BP1 abrogates the effect of rapamycin on cyclin D1 expression and increases the polysomal association of the cyclin D1 mRNA. Our data identify 4E-BP1 as a key regulator of cyclin D1 expression, indicate that this effect is not mediated through the changes in cytoplasmic levels of cyclin D1 mRNA and suggest that, in some cell types, interfering with the amino acid input to mTORC1, rather than using rapamycin, may inhibit proliferation.

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Section: Discussionmentioning

confidence: 99%

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

2007

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“…We showed that after 4 hours of hypoxia the disruption of eIF4F may also occur as a result of redistribution of eIF4E and the eIF4E translocator protein (4E-T) into either the nucleus or the recently discovered cytoplasmic bodies of mRNA processing (P-bodies; refs. 79,80). Translocation of eIF4E into either of these cellular locations makes it unavailable to participate in translation initiation.…”

Section: Mtor-independent Regulation Of Eif4fmentioning

confidence: 99%

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

Koumenis

Wouters

2006

Molecular Cancer Research

209

170

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Poor oxygenation (hypoxia) is present in the majority of human tumors and is associated with poor prognosis due to the protection it affords to radiotherapy and chemotherapy. Hypoxia also elicits multiple cellular response pathways that alter gene expression and affect tumor progression, including two recently identified separate pathways that strongly suppress the rates of mRNA translation during hypoxia. The first pathway is activated extremely rapidly and is mediated by phosphorylation and inhibition of the eukaryotic initiation factor 2A. Phosphorylation of this factor occurs as part of a coordinated endoplasmic reticulum stress response program known as the unfolded protein response and activation of this program is required for hypoxic cell survival and tumor growth. Translation during hypoxia is also inhibited through the inactivation of a second eukaryotic initiation complex, eukaryotic initiation factor 4F. At least part of this inhibition is mediated through a Redd1 and tuberous sclerosis complex 1/2 -dependent inhibition of the mammalian target of rapamycin kinase. Inhibition of mRNA translation is hypothesized to affect the cellular tolerance to hypoxia in part by promoting energy homeostasis. However, regulation of translation also results in a specific increase in the synthesis of a subset of hypoxia-induced proteins. Consequently, both arms of translational control during hypoxia influence gene expression and phenotype. These hypoxic response pathways show differential activation requirements that are dependent on the level of oxygenation and duration of hypoxia and are themselves highly dynamic. Thus, the severity and duration of hypoxia can lead to different biological and therapeutic consequences. (Mol Cancer Res 2006;4(7):423 -36)

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“…In the nucleus, the monomeric form of eIF4E colocalizes with splicing factors in nuclear speckles, 18 suggesting a possible role in mRNA processing. Available data indicate that eIF4E binds capped transcripts in the nucleus following the pioneering round of translation, or in the cytoplasm.…”

Section: Translation Initiation Apparatusmentioning

confidence: 99%

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

Polunovsky¹,

Bitterman²

2006

RNA Biology

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A novel shuttling protein, 4E-T, mediates the nuclear import of the mRNA 5' cap-binding protein, eIF4E

Cited by 180 publications

References 80 publications

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways

The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways

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