Date of Award

2010

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Howe, Philip

Subject Headings

Transforming growth factors-beta, Epithelium, Mesenchyme, TGFß, EMT, Dab2, ILEI, HnRNP, Metastasis

Abstract

TGFß induces epithelial-mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration, a process fundamental during embryonic development and one that is reactivated in a variety of diseases including fibrosis and cancer. Despite extensive transcriptomic profiling, identification of TGFß-inducible, EMT-specific genes has met with limited success. Here, we report a novel post-transcriptional pathway by which TGFß modulates expression of EMT-specific proteins and EMT itself. We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33 nucleotides (nt) TGF-beta-activated translation (BAT) element in the 3'-untranslated regions (UTRs) of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and repress their translation. TGFß activation leads to phosphorylation at Ser43 of hnRNP E1 by protein kinase Bß/Akt2 inducing its release from the BAT element and reversal of translational silencing of Dab2 and ILEI mRNAs. Further, using a genome-wide combinatorial approach involving polysome profiling and RIP-Chip analyses we have identified a cohort of four mRNAs (Rhox5, Ube3A, Prl2c4 and IL-11Ralpha2) that follow the same pattern of regulation as Dab2 and ILEI. Each of the identified targets mRNA harbors a functional BAT element in the 3'-UTR and is required for TGFß-induced EMT. Modulation of hnRNP E1 expression or its post-translational modification alters TGFß-mediated translational activation of the target transcripts and EMT in vitro and in vivo. This cohort of mRNAs may represent a new TGFß responsive and hnRNP E1-mediated posttranscriptional regulon that regulates TGFß-induced EMT during development and metastatic progression of tumors in a temporal and expedited fashion. The autocrine response of cells to TGFß-induced Akt2 activation and subsequent translational activation of EMT inducer transcripts may represent a novel mechanism through which the increased TGFß expression in tumor cells contribut

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