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Translational regulation of inhibin ?A by TGF? via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells.

ABSTRACT: The epithelial-to-mesenchymal transition (EMT) is a cellular process that functions during embryonic development and tissue regeneration, thought to be aberrantly activated in epithelial-derived cancer and has an important role in the process of metastasis. The transforming growth factor (TGF)-? signaling pathway is a key inducer of EMT and we have elucidated a posttranscriptional mechanism by which TGF? modulates expression of select transcripts via the RNA-binding protein hnRNP E1 during EMT. One such transcript inhibin ?A is a member of the TGF? superfamily. Here, we show by polysome profiling that inhibin ?A is translationally regulated by TGF? via hnRNP E1. TGF? treatment or knockdown of hnRNP E1 relieves silencing of the inhibin ?A transcript, resulting in increased protein expression and secreted levels of the inhibin ?A homodimer, activin A. Our data indicate that the translational upregulation of inhibin ?A enhances the migration and invasion of cells that have undergone an EMT and promotes cancer progression in vivo.

SUBMITTER: Howley BV

PROVIDER: S-EPMC4688046 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Translational regulation of inhibin βA by TGFβ via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells.

Howley B V BV Hussey G S GS Link L A LA Howe P H PH

Oncogene 20150622 13

The epithelial-to-mesenchymal transition (EMT) is a cellular process that functions during embryonic development and tissue regeneration, thought to be aberrantly activated in epithelial-derived cancer and has an important role in the process of metastasis. The transforming growth factor (TGF)-β signaling pathway is a key inducer of EMT and we have elucidated a posttranscriptional mechanism by which TGFβ modulates expression of select transcripts via the RNA-binding protein hnRNP E1 during EMT. ...[more]

PMID: 26096938

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Project description:Regulation of gene expression at the post-transcriptional level plays an indispensable role during TGFbeta-induced EMT and metastasis. This regulation involves a transcript-selective translational regulatory pathway in which a ribonucleoprotein (mRNP) complex, consisting of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) and eukaryotic elongation factor 1A1 (eEF1A1), binds to a 3M-bM-^@M-^Y-UTR regulatory BAT (TGFM-NM-2 activated translation) element and silences translation of Dab2 and ILEI mRNAs, two transcripts which are involved in mediating EMT. TGFbeta activates a kinase cascade terminating in the phosphorylation of hnRNP E1, by isoform-specific stimulation of protein kinase B/Akt2, inducing the release of the mRNP complex from the 3M-bM-^@M-^Y-UTR element, resulting in the reversal of translational silencing and increased expression of Dab2 and ILEI transcripts. We adopted a combinatorial approach involving polysome profiling and RIP-Chip analyses using hnRNP E1 and filtered the array data based on the regulatory mechanism of Dab2 and ILEI. This led to the identification and validation of a cohort of target mRNAs that follow the same pattern of regulation as Dab2 and ILEI. To identify potential target mRNA transcripts that are translationally regulated by hnRNP E1 in a TGF-beta-dependent manner, we adopted a combinatorial approach involving expression profiling analyses and RNA immunoprecipitation analysis (RIP-Chip). We performed a screen using: 1) total mRNA and 2) RNA isolated from monosomal (non-translating) versus polysomal (translating) fractions from TGF-beta-treated (24 h) and non-treated NMuMG cells and from the hnRNP E1 knockdown derivative (E1KD), that undergo constitutive EMT even in the absence of TGF-beta. In addition, we screened for transcripts that selectively interact with hnRNP E1 in NMuMG cells under unstimulated conditions and subsequently lose their temporal association following TGF-beta stimulation. The samples were individually hybridized to Affymetrix GeneChipM-BM-. Mouse Genome 430 2.0 arrays.

Dataset Information

Translational regulation of inhibin ?A by TGF? via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells.

Publications

Translational regulation of inhibin βA by TGFβ via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells.

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