Abstract
Transforming growth factor-β (TGF-β) induces epithelial–mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration1,2,3,4,5. Despite extensive transcriptomic profiling, the identification of TGF-β-inducible, EMT-specific genes has met with limited success. Here we identify a post-transcriptional pathway by which TGF-β modulates the expression of EMT-specific proteins and of EMT itself. We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-β-activated translation (BAT) element in the 3′ untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation. TGF-β activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bβ/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs. Modulation of hnRNP E1 expression or its post-translational modification alters the TGF-β-mediated reversal of translational silencing of the target transcripts and EMT. These results suggest the existence of a TGF-β-inducible post-transcriptional regulon that controls EMT during the development and metastatic progression of tumours.
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Acknowledgements
We thank Donna M. Driscoll, Barsanjit Mazumder and members of our laboratory for helpful discussions and critical insights. We value the assistance of Michael T. Kinter and Belinda Willard for liquid chromatography–mass spectrometry; of Judith A. Drazba and John Peterson for imaging; and of Michael Budiman for fast performance liquid chromatography. We thank Rakesh Kumar for the gift of the GST–hnRNP E1 construct, Takashi Kobayashi for the gifts of mouse pCMV14-hnRNP E1-Flag and psiRNA-hH1neo-mouse hnRNP E1, and Harold Moses for giving us the EpRas cell line. This work was supported by grants CA55536 and CA80095 from the National Cancer Institute to P.H.H. A.C. is supported by an American Heart Association (Ohio Valley Affiliate) Pre-doctoral Fellowship 075080B.
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P.H.H. directed the project. G.J. made the initial observation of uncoupled Dab2 mRNA and protein expression levels. G.S.H. performed the experiments in the EpRas cell line. P.S.R. contributed to the polysome profiling and PatSearch analyses. P.L.F. provided critical insights and expertise throughout. G.J., G.S.H. and A.C. made all the reagents. A.C. performed most of the experiments. P.H.H. and A.C. analysed the data and wrote the paper. All authors reviewed the manuscript.
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Chaudhury, A., Hussey, G., Ray, P. et al. TGF-β-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol 12, 286–293 (2010). https://doi.org/10.1038/ncb2029
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DOI: https://doi.org/10.1038/ncb2029
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