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PMID: 20154680 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI.

Nature cell biology ·Vol. 12 ·No. 3 ·2010-03-00 ·Pages 286-93

Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH

Abstract

Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration. Despite extensive transcriptomic profiling, the identification of TGF-beta-inducible, EMT-specific genes has met with limited success. Here we identify a post-transcriptional pathway by which TGF-beta 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-beta-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-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/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-beta-mediated reversal of translational silencing of the target transcripts and EMT. These results suggest the existence of a TGF-beta-inducible post-transcriptional regulon that controls EMT during the development and metastatic progression of tumours.

MeSH Terms
3' Untranslated Regions/physiology Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport/genetics,metabolism Animals Apoptosis Regulatory Proteins Cadherins/metabolism Carrier Proteins/genetics,metabolism Cell Line, Transformed Cell Transdifferentiation/physiology Cytokines/genetics,metabolism DNA-Binding Proteins Epithelial Cells/pathology Female Gene Expression/drug effects,genetics Gene Expression Regulation, Neoplastic/physiology Insulin/pharmacology Mammary Glands, Animal/pathology Mesoderm/pathology Mice Neoplasm Proteins/genetics,metabolism Phosphorylation/drug effects,physiology Polyribosomes/metabolism Protein Binding/genetics Protein Biosynthesis/physiology Protein Isoforms/metabolism Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins c-akt/metabolism RNA, Messenger/genetics,metabolism RNA, Small Interfering/genetics RNA-Binding Proteins Signal Transduction/drug effects Transforming Growth Factor beta/pharmacology Vimentin/metabolism
Chemicals
3' Untranslated Regions Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport Apoptosis Regulatory Proteins Cadherins Carrier Proteins Cdh2 protein, mouse Cytokines DNA-Binding Proteins Dab2 protein, mouse Fam3c protein, mouse Insulin Neoplasm Proteins Pcbp1 protein, mouse Protein Isoforms Protein Kinase Inhibitors RNA, Messenger RNA, Small Interfering RNA-Binding Proteins Transforming Growth Factor beta Vimentin Akt2 protein, mouse Proto-Oncogene Proteins c-akt
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Chaudhury Arindam
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Hussey George S
Ray Partho S
Jin Ge
Fox Paul L
Howe Philip H
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Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb2029
Published
2010-03-00
Epub
2010-00-14
Pages
286-93
Language
English
Region
England
NLM ID
100890575
PMCID
PMC2830561
Subset
IM
Grants
NCI NIH HHS · R01 CA080095 · United States
NCI NIH HHS · CA55536 · United States
NCI NIH HHS · CA80095 · United States
NCI NIH HHS · R01 CA080095-12 · United States
NCI NIH HHS · R01 CA154663 · United States
NCI NIH HHS · R01 CA055536-19 · United States
NCI NIH HHS · R01 CA055536 · United States
NCI NIH HHS · R01 CA154663-01 · United States
NCI NIH HHS · R01 CA055536-20 · United States
External Links
PubMed source DOI: 10.1038/ncb2029 PMC Full Text View journal details
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