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

View Article: PubMed Central - PubMed

ABSTRACT

The importance of translational regulation in tumour biology is increasingly appreciated. Here, we leverage polyribosomal profiling to prospectively define translational regulatory programs underlying epithelial-to-mesenchymal transition (EMT) in breast epithelial cells. We identify a group of ten translationally regulated drivers of EMT sharing a common GU-rich cis-element within the 3′-untranslated region (3′-UTR) of their mRNA. These cis-elements, necessary for the regulatory activity imparted by these 3′-UTRs, are directly bound by the CELF1 protein, which itself is regulated post-translationally during the EMT program. CELF1 is necessary and sufficient for both mesenchymal transition and metastatic colonization, and CELF1 protein, but not mRNA, is significantly overexpressed in human breast cancer tissues. Our data present an 11-component genetic pathway, invisible to transcriptional profiling approaches, in which the CELF1 protein functions as a central node controlling translational activation of genes driving EMT and ultimately tumour progression.

No MeSH data available.


Working model illustrating translational regulation at play in TGF-β-mediated EMT of breast epithelial cells.TGF-β induces CELF1 protein expression, which in turn induces translational upregulation of a cohort of mRNAs that are either necessary (blue) or both necessary and sufficient (green) to induce EMT. The model incorporates results of our genetic ordering analysis (Fig. 4), which suggests PPARGC1A, FOSB and JUNB initiate a feed-forward loop with CELF1 through an indirect and as-yet-undefined mechanism.
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f8: Working model illustrating translational regulation at play in TGF-β-mediated EMT of breast epithelial cells.TGF-β induces CELF1 protein expression, which in turn induces translational upregulation of a cohort of mRNAs that are either necessary (blue) or both necessary and sufficient (green) to induce EMT. The model incorporates results of our genetic ordering analysis (Fig. 4), which suggests PPARGC1A, FOSB and JUNB initiate a feed-forward loop with CELF1 through an indirect and as-yet-undefined mechanism.

Mentions: We propose a novel post-transcriptional regulon56 active in EMT and cancer progression (Fig. 8), adding to the established catalogue of post-transcriptional regulatory events underlying EMT57585960. It is important to reiterate that the vast majority of the components of the regulon that we have identified are defined by either no change in or reduction of relative total mRNA expression in publicly available breast cancer transcriptional data sets. Although a full characterization of each of the components of the regulon is beyond the scope of this work, it is reasonable to consider the possibility that in future studies many of CELF1's downstream targets will be found to be similarly misexpressed at only the protein level in primary human breast cancers. Our findings underscore the potential importance of discrete post-transcriptional regulons in the context of fundamental processes underlying tumourigenesis and cancer progression.


CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT
Working model illustrating translational regulation at play in TGF-β-mediated EMT of breast epithelial cells.TGF-β induces CELF1 protein expression, which in turn induces translational upregulation of a cohort of mRNAs that are either necessary (blue) or both necessary and sufficient (green) to induce EMT. The model incorporates results of our genetic ordering analysis (Fig. 4), which suggests PPARGC1A, FOSB and JUNB initiate a feed-forward loop with CELF1 through an indirect and as-yet-undefined mechanism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121338&req=5

f8: Working model illustrating translational regulation at play in TGF-β-mediated EMT of breast epithelial cells.TGF-β induces CELF1 protein expression, which in turn induces translational upregulation of a cohort of mRNAs that are either necessary (blue) or both necessary and sufficient (green) to induce EMT. The model incorporates results of our genetic ordering analysis (Fig. 4), which suggests PPARGC1A, FOSB and JUNB initiate a feed-forward loop with CELF1 through an indirect and as-yet-undefined mechanism.
Mentions: We propose a novel post-transcriptional regulon56 active in EMT and cancer progression (Fig. 8), adding to the established catalogue of post-transcriptional regulatory events underlying EMT57585960. It is important to reiterate that the vast majority of the components of the regulon that we have identified are defined by either no change in or reduction of relative total mRNA expression in publicly available breast cancer transcriptional data sets. Although a full characterization of each of the components of the regulon is beyond the scope of this work, it is reasonable to consider the possibility that in future studies many of CELF1's downstream targets will be found to be similarly misexpressed at only the protein level in primary human breast cancers. Our findings underscore the potential importance of discrete post-transcriptional regulons in the context of fundamental processes underlying tumourigenesis and cancer progression.

View Article: PubMed Central - PubMed

ABSTRACT

The importance of translational regulation in tumour biology is increasingly appreciated. Here, we leverage polyribosomal profiling to prospectively define translational regulatory programs underlying epithelial-to-mesenchymal transition (EMT) in breast epithelial cells. We identify a group of ten translationally regulated drivers of EMT sharing a common GU-rich cis-element within the 3′-untranslated region (3′-UTR) of their mRNA. These cis-elements, necessary for the regulatory activity imparted by these 3′-UTRs, are directly bound by the CELF1 protein, which itself is regulated post-translationally during the EMT program. CELF1 is necessary and sufficient for both mesenchymal transition and metastatic colonization, and CELF1 protein, but not mRNA, is significantly overexpressed in human breast cancer tissues. Our data present an 11-component genetic pathway, invisible to transcriptional profiling approaches, in which the CELF1 protein functions as a central node controlling translational activation of genes driving EMT and ultimately tumour progression.

No MeSH data available.