Translational Control in Cancer

Robichaud, Nathaniel; Sonenberg, Nahum; Ruggero, Davide; Schneider, Robert J.

doi:10.1101/cshperspect.a032896

Cited by 205 publications

(184 citation statements)

References 163 publications

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“…Emerging evidence suggests that regulatory control at the level of mRNA translation contributes significantly to gene expression and function (1)(2)(3)(4). Consistent with this evidence, recent findings indicate that coordinated changes in post-transcriptional regulatory networks can alter cellular phenotype and behavior (2,5). A core cellular process underlying development, tumor metastasis, and tumor radiation and chemoresistance is epithelial to mesenchymal transition (EMT) (6,7).…”

Section: Introductionmentioning

confidence: 84%

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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Section: Introductionmentioning

confidence: 84%

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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“…Translation is a fundamental process for all forms of life because it plays a central role in gene expression, and translational control critically contributes to the composition and quantity of a cell's proteome (2)(3)(4)(5). Recently, dysregulation of translational control has been recognized as a cause of malfunctioning of other key cellular processes, which may lead to the onset and development of different types of cancer (6)(7)(8)(9)(10). Here, we discuss current research shedding light on the interplay between translation and autophagy and its involvement in cancer.…”

Section: Introductionmentioning

confidence: 99%

Autophagy Regulation by the Translation Machinery and Its Implications in Cancer

et al. 2020

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Various metabolic pathways and molecular processes in the cell act intertwined, and dysregulating the interplay between some of them may lead to cancer. It is only recently that defects in the translation process, i.e., the synthesis of proteins by the ribosome using a messenger (m)RNA as a template and translation factors, have begun to gain strong attention as a cause of autophagy dysregulation with effects in different maladies, including cancer. Autophagy is an evolutionarily conserved catabolic process that degrades cytoplasmic elements in lysosomes. It maintains cellular homeostasis and preserves cell viability under various stress conditions, which is crucial for all eukaryotic cells. In this review, we discuss recent advances shedding light on the crosstalk between the translation and the autophagy machineries and its impact on tumorigenesis. We also summarize how this interaction is being the target for novel therapies to treat cancer.

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“…Accelerated cellular division and macromolecular growth of tumors is dependent on robust protein synthesis. To meet this need, ribosome biogenesis and translation rates are frequently elevated in cancer cells 1 . Increased translation in cancer cells is often driven by activation of the mTORC1 pathway 1 .…”

Section: Introductionmentioning

confidence: 99%

ARF suppresses 5’-terminal oligopyrimidine mRNA translation

Cottrell

Weber

2020

Preprint

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6Tumor cells require nominal increases in protein synthesis in order to maintain high proliferation rates. As 7 such, tumor cells must acquire enhanced ribosome production. How many of the mutations in tumor cells 8 ultimately achieve this aberrant production is largely unknown. The gene encoding ARF is the most commonly 9 deleted gene in human cancer. ARF plays a significant role in regulating ribosomal RNA synthesis and 10 processing, ribosome export into the cytoplasm, and global protein synthesis. Utilizing ribosome profiling, we 11 show that ARF is a major suppressor of 5'-terminal oligopyrimidine mRNA translation. Genes with increased 12 translational efficiency following loss of ARF include many ribosomal proteins and translation factors. 13 Knockout of p53 caused a similar increase in 5'-TOP mRNA translation. The 5'-TOP regulators mTORC1, eIF4G1 14 and LARP1 are dysregulated in ARF and p53 null cells. 15 16 17 18

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Translational Control in Cancer

Cited by 205 publications

References 163 publications

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

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

Autophagy Regulation by the Translation Machinery and Its Implications in Cancer

ARF suppresses 5’-terminal oligopyrimidine mRNA translation

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