Molecular Pathways: The eIF4F Translation Initiation Complex—New Opportunities for Cancer Treatment

Malka-Mahieu, Hélène; Newman, Michelle R.; Désaubry, Laurent; Robert, Caroline; Vagner, Stéphan

doi:10.1158/1078-0432.ccr-14-2362

Cited by 86 publications

(86 citation statements)

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“…Additional experiments are required to establish whether AID and other proteins involved in CSR are regulated at the level of translation. Cap-dependent translation is an attractive target for cancer therapy and efforts are underway to develop smallmolecule inhibitors of eIF4F components (eIF4E, eIF4G, eIF4A) for oncology (11,26,(43)(44)(45). Further study of this pathway may provide mechanistic insight into how the immune system will be FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

The mTORC1/4E-BP/eIF4E Axis Promotes Antibody Class Switching in B Lymphocytes

Chiu

Jackson

et al. 2019

The Journal of Immunology

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During an adaptive immune response, activated mature B cells give rise to Ab-secreting plasma cells to fight infection. B cells undergo Ab class switching to produce different classes of Abs with varying effector functions. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is activated during this process, and disrupting mTOR complex 1 (mTORC1) in B cells impairs class switching by a poorly understood mechanism. In particular, it is unclear which mTORC1 downstream substrates control this process. In this study, we used an in vitro murine model in which the mTORC1 inhibitor rapamycin, when added after a B cell has committed to divide, suppresses class switching while preserving proliferation. Investigation of mTORC1 substrates revealed a role for eukaryotic translation initiation factor 4E (eIF4E) and eIF4E-binding proteins in class switching. Mechanistically, we show that genetic or pharmacological disruption of eIF4E binding to eIF4G reduced cap-dependent translation, which specifically affected the expression of activation-induced cytidine deaminase protein but not Aicda mRNA. This translational impairment decreased Ab class switching independently of proliferation. These results uncover a previously undescribed role for mTORC1 and the eIF4E-binding proteins/eIF4E axis in activation-induced cytidine deaminase protein expression and Ab class switching in mouse B cells, suggesting that cap-dependent translation regulates key steps in B cell differentiation.

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Section: Discussionmentioning

confidence: 99%

The mTORC1/4E-BP/eIF4E Axis Promotes Antibody Class Switching in B Lymphocytes

Chiu

Jackson

et al. 2019

The Journal of Immunology

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“…Among cap-dependent mRNA transcripts, those that are more sensitive to decreased eIF4F activity are enriched in cell cycle and survival factors. Pharmacological and genetic studies have validated eIF4F as an oncogenic node and targetable vulnerability in cancer cells (Malka-Mahieu et al, 2017). Importantly, 4E-BP phosphorylation is inhibited to a greater extent by TORKi than by rapamycin (Figure 2), and the more penetrating inhibition of translation initiation by TORKi contributes to the more profound inhibition of cell growth and proliferation by these agents.…”

Section: The Pi3k Signaling Networkmentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,977

1,658

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Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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“…It is thus tempting to speculate that additional specialized translational complexes remain to be discovered, both in normal cellular function and within the diseased or transformed state. From the latter perspective, a more robust mechanistic understanding of analogous specialized mechanisms of translation may reveal novel vulnerabilities that may be exploited in the clinic, especially given the initial promise within clinical trials of drugs targeting canonical translation initiation as a bulk process (53,54),…”

Section: Discussionmentioning

confidence: 99%

CELF1 is an EIF4E binding protein that promotes translation of epithelial-mesenchymal transition effector mRNAs

Chaudhury

Pal

Kongchan

et al. 2019

Preprint

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Mounting evidence is revealing a granularity within gene regulation that occurs at the level of mRNA translation. Within mammalian cells, canonical cap-dependent mRNA translation is dependent upon the interaction between the m 7 G cap-binding protein eukaryotic initiation factor 4E (eIF4E) and the scaffolding protein eukaryotic initiation factor 4G (eIF4G), the latter of which facilitates pre-translation initiation complex assembly, mRNA circularization, and ultimately ribosomal scanning. In breast epithelial cells, we previously demonstrated that the CELF1 RNA-binding protein promotes the translation of epithelial to mesenchymal transition (EMT) effector mRNAs containing GU-rich elements (GREs) within their 3' untranslated regions (UTRs). Here we show that within this context, CELF1 directly binds to both the eIF4E capbinding protein and Poly(A) binding protein (PABP), promoting translation of GRE-containing mRNAs in mesenchymal cells. Disruption of this CELF1/eIF4E interaction inhibits both EMT induction and experimental metastasis. Our findings illustrate a novel way in which noncanonical mechanisms of translation initiation underlie transitional cellular states within the context of development or human disease.It has now been well-documented that both oncogenes and signaling pathways regulating expression of these oncogenes together converge on the regulation of mRNA translation (2,15).Indeed, within the process of cellular transformation, mechanisms at each stage of translation and the ribosomal machinery may be co-opted to fostering translation that perpetuates the oncogenic program (16)(17)(18). This motivated us to more closely examine how CELF1 regulates translation of GRE-containing EMT effector mRNAs during EMT of breast epithelial cells. Results CELF1 interacts directly with eIF4E and PABP at the m 7 G cap, independent of intact eIF4G1Our previous work suggested that CELF1's control of GU-rich element-containing EMT effector mRNA translation is mediated at the level of 5' m 7 G cap-dependent translation initiation (10). We first confirmed and extended these findings by examining an additional CELF1 regulatory target within this context. We fused the 3' UTRs of a subset of GRE-containing mRNAs (JUNB, CRLF1, SNAI1, and SSBP2) downstream of the Renilla luciferase coding sequence in the pRL-TK-CXCR4-6x (19) reporter plasmid (Figure 1a). Transfection of the GREcontaining 3' UTR reporters into MCF10A cells, either untreated or treated with TGF-β to induce EMT, revealed a significant increase in reporter activity specific to treated cells Figure 1a), independent of any differences in relative mRNA expression (Figure 1b). In parallel, we built a battery of bicistronic constructs in which the same thymidine kinase promoter was utilized to drive expression of the firefly luciferase coding sequence, followed by the encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES), the Renilla luciferase open reading frame and individual GRE-containing 3' UTRs (pFR-EMCV) (Figure 1c). In contrast to cap-depen...

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Molecular Pathways: The eIF4F Translation Initiation Complex—New Opportunities for Cancer Treatment

Cited by 86 publications

References 50 publications

The mTORC1/4E-BP/eIF4E Axis Promotes Antibody Class Switching in B Lymphocytes

The mTORC1/4E-BP/eIF4E Axis Promotes Antibody Class Switching in B Lymphocytes

The PI3K Pathway in Human Disease

CELF1 is an EIF4E binding protein that promotes translation of epithelial-mesenchymal transition effector mRNAs

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