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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions / physiology
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism*
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Animals
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Apoptosis Regulatory Proteins
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Cadherins / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Transformed
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Cell Transdifferentiation / physiology*
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Cytokines / genetics
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Cytokines / metabolism*
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DNA-Binding Proteins
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Epithelial Cells / pathology
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Female
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Gene Expression / drug effects
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Gene Expression / genetics
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Gene Expression Regulation, Neoplastic / physiology*
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Insulin / pharmacology
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Mammary Glands, Animal / pathology
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Mesoderm / pathology
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Polyribosomes / metabolism
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Protein Binding / genetics
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Protein Biosynthesis / physiology
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Protein Isoforms / metabolism
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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RNA-Binding Proteins
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Signal Transduction / drug effects
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Transforming Growth Factor beta / pharmacology*
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Vimentin / metabolism
Substances
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3' Untranslated Regions
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Apoptosis Regulatory Proteins
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Cadherins
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Carrier Proteins
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Cdh2 protein, mouse
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Cytokines
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DNA-Binding Proteins
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Dab2 protein, mouse
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Fam3c protein, mouse
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Insulin
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Neoplasm Proteins
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Pcbp1 protein, mouse
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Protein Isoforms
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Protein Kinase Inhibitors
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RNA, Messenger
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RNA, Small Interfering
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RNA-Binding Proteins
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Transforming Growth Factor beta
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Vimentin
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Akt2 protein, mouse
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Proto-Oncogene Proteins c-akt