Date of Award
Biological, Geological and Environmental Sciences
Transforming growth factors-beta, Epithelium, Mesenchyme, TGF├ƒ, EMT, Dab2, ILEI, HnRNP, Metastasis
TGF├ƒ 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 TGF├ƒ-inducible, EMT-specific genes has met with limited success. Here, we report a novel post-transcriptional pathway by which TGF├ƒ 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. TGF├ƒ activation leads to phosphorylation at Ser43 of hnRNP E1 by protein kinase B├ƒ/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 TGF├ƒ-induced EMT. Modulation of hnRNP E1 expression or its post-translational modification alters TGF├ƒ-mediated translational activation of the target transcripts and EMT in vitro and in vivo. This cohort of mRNAs may represent a new TGF├ƒ responsive and hnRNP E1-mediated posttranscriptional regulon that regulates TGF├ƒ-induced EMT during development and metastatic progression of tumors in a temporal and expedited fashion. The autocrine response of cells to TGF├ƒ-induced Akt2 activation and subsequent translational activation of EMT inducer transcripts may represent a novel mechanism through which the increased TGF├ƒ expression in tumor cells contribut
Chaudhury, Arindam, "Transforming Growth Factor-Beta (TGFΒ)-Mediated Post-Transcriptional Regulation of Epithelial-Mesenchymal Transdifferentiation (EMT)" (2010). ETD Archive. 63.