CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT

Chaudhury, Arindam; Cheema, Shebna; Fachini, Joseph M.; Kongchan, Natee; Lu, Gui-Fu; Simon, Lukas M.; Wang, Tao; Mao, Sufeng; Rosen, Daniel; Ittmann, Michael; Hilsenbeck, Susan G.; Shaw, Chad A.; Neilson, Joel R.

doi:10.1038/ncomms13362

Cited by 59 publications

(68 citation statements)

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“…Reciprocal coimmunoprecipitation experiments demonstrated that CELF1 interacts with eIF4E, and that this interaction is strengthened by eIF4E phosphorylation (Figure 3b). Indeed, translation of CELF1's previously defined EMT effector targets (10) was blocked in the S209A mutant expressing cells (Figure 3c-e), consistent with the notion that eIF4E phosphorylation is required for CELF1's function as a promoter of mRNA translation and EMT driver.…”

Section: Phosphorylation Of Eif4e Is Required For Celf1-driven Emt Insupporting

confidence: 82%

“…Indeed, overexpression of the CELF1Δ365-371 (YAAAALP) mutant failed to induce EMT in MCF10A cells despite comparable levels of expression between the mutant and wild-type CELF1 proteins To determine whether the importance of the CELF1/eIF4E interaction was limited to EMT in vitro, we next assessed the importance of this interaction in a model of experimental metastasis. Overexpression of CELF1 induces experimental lung metastasis from the normally tumorigenic but non-metastatic MCF10AT1 cell line (10,34). Consistent with our own previously described work, ectopic expression of wild-type CELF1 within MCF10AT1 cells injected into the tail vein of nude mice conferred these cells with the ability to rapidly induce lung colonization in the animals tested.…”

Section: Interaction Of Celf1 and Eif4e Is Required For Celf1-driven mentioning

confidence: 99%

“…The MCF10A cell line was obtained from the ATCC (Manassas, VA) and cultured as described previously (10…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…Cell lysis and immunoblotting was performed as described previously (10,55). Supplementary Table 1 provides the list and associated information of antibodies used in the current study.…”

Section: Cell Lysis Immunoblot and Immunoprecipitationmentioning

confidence: 99%

“…Since the metastasis and resistance to insult associated with cellular dedifferentiation are the foremost cause of cancer lethality (8,9), it is critical to develop a better understanding of the mechanisms by which EMT, and thus these two characteristics, are promoted. We previously defined a translational regulatory circuit driving EMT in vitro, and cancer progression in vivo, in breast epithelial cells (10). The key regulator of this circuit is the RNA binding protein CELF1, which promotes translation of EMT effector mRNAs by binding to GU-rich elements (GREs) within the 3' untranslated regions (UTRs) of these mRNAs.…”

Section: Introductionmentioning

confidence: 99%

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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: Phosphorylation Of Eif4e Is Required For Celf1-driven Emt Insupporting

confidence: 82%

Section: Interaction Of Celf1 and Eif4e Is Required For Celf1-driven mentioning

confidence: 99%

“…The MCF10A cell line was obtained from the ATCC (Manassas, VA) and cultured as described previously (10…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…Cell lysis and immunoblotting was performed as described previously (10,55). Supplementary Table 1 provides the list and associated information of antibodies used in the current study.…”

Section: Cell Lysis Immunoblot and Immunoprecipitationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Chaudhury

Pal

Kongchan

et al. 2019

Preprint

Self Cite

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The role and molecular mechanism of Trop2 induced epithelial‐mesenchymal transition through mediated β‐catenin in gastric cancer

et al. 2019

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The present study elucidates the potential role of Trop2 in tumor invasion and the promotion of epithelial‐mesenchymal transition (EMT) when binding β‐catenin in GC. The role of Trop2 in promoting EMT in GC cells was examined by a variety of experimental assays. Moreover, the underlying molecular mechanism of Trop2 in promoting EMT was studied by in vivo and in vitro assays. The Trop2 expression in relation to tumor metastasis status was detected by IHC in 248 cases of GC tissues and 86 cases of matched adjacent tissues. Trop2 promoted the metastasis and induces EMT in GC. Meanwhile, the elevated protein levels of Trop2 and mesenchymal markers were also found in the TGF‐β1‐induced EMT model in GC cells. Importantly, Trop2 physically bound and activated β‐catenin to promote EMT; moreover, Trop2 increased the accumulation of β‐catenin in the nucleus to accelerate metastasis in GC cells. Inhibition of Trop2 expression in GC cells prevented the migration and invasion of GC cells in vivo. Trop2+/vimentin+ expression was higher in GC tissues than that in matched adjacent tissues, and Trop2+/vimentin+ expression in GC was associated with the differentiation, TNM stage, and distant metastases. These sets of data reveal a novel regulatory network of Trop2 in EMT and GC metastasis, suggesting Trop2 as a useful marker for inducing EMT and metastasis of GC, which may help to lead a better understanding of the pathogenesis of the GC.

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Emerging roles of RNA‐binding proteins in diabetes and their therapeutic potential in diabetic complications

Nutter

Kuyumcu‐Martinez

2017

WIREs RNA

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Diabetes is a debilitating health care problem affecting 422 million people around the world. Diabetic patients suffer from multisystemic complications that can cause mortality and morbidity. Recent advancements in high-throughput next-generation RNA-sequencing and computational algorithms led to the discovery of aberrant posttranscriptional gene regulatory programs in diabetes. However, very little is known about how these regulatory programs are mis-regulated in diabetes. RNA-binding proteins (RBPs) are important regulators of posttranscriptional RNA networks, which are also dysregulated in diabetes. Human genetic studies provide new evidence that polymorphisms and mutations in RBPs are linked to diabetes. Therefore, we will discuss the emerging roles of RBPs in abnormal posttranscriptional gene expression in diabetes. Questions that will be addressed are: Which posttranscriptional mechanisms are disrupted in diabetes? Which RBPs are responsible for such changes under diabetic conditions? How are RBPs altered in diabetes? How does dysregulation of RBPs contribute to diabetes? Can we target RBPs using RNA-based methods to restore gene expression profiles in diabetic patients? Studying the evolving roles of RBPs in diabetes is critical not only for a comprehensive understanding of diabetes pathogenesis but also to design RNA-based therapeutic approaches for diabetic complications. WIREs RNA 2018, 9:e1459. doi: 10.1002/wrna.1459 This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing Translation > Translation Regulation.

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CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT

Cited by 59 publications

References 68 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

The role and molecular mechanism of Trop2 induced epithelial‐mesenchymal transition through mediated β‐catenin in gastric cancer

Emerging roles of RNA‐binding proteins in diabetes and their therapeutic potential in diabetic complications

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