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Transforming Growth Factor-Beta (TGFΒ)-Mediated Post-Transcriptional Regulation of Epithelial-Mesenchymal Transdifferentiation (EMT)

Chaudhury, Arindam
http://rave.ohiolink.edu/etdc/view?acc_num=csu1268963035

Abstract Details

2010, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Science.
TGFΒ 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 TGFΒ-inducible, EMT-specific genes has met with limited success. Here, we report a novel post-transcriptional pathway by which TGFΒ 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. TGFΒ activation leads to phosphorylation at Ser43 of hnRNP E1 by protein kinase Bβ/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-11Rα2) 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 TGFΒ-induced EMT. Modulation of hnRNP E1 expression or its post-translational modification alters TGFΒ-mediated translational activation of the target transcripts and EMT in vitro and in vivo. This cohort of mRNAs may represent a new TGFΒ responsive and hnRNP E1-mediated posttranscriptional regulon that regulates TGFΒ-induced EMT during development and metastatic progression of tumors in a temporal and expedited fashion. The autocrine response of cells to TGFΒ-induced Akt2 activation and subsequent translational activation of EMT inducer transcripts may represent a novel mechanism through which the increased TGFΒ expression in tumor cells contributes to cancer progression.
Philip H. Howe, PhD (Advisor)
Paul L Fox, PhD (Committee Member)
Donna M Driscoll, PhD (Committee Chair)
Clemencia Colmenares, PhD (Committee Co-Chair)
Xiaoxia Li, PhD (Committee Member)
Crystal Weyman, PhD (Committee Member)
Barsanjit Mazumder, PhD (Committee Member)
215 p.
Biochemistry; Biology; Biomedical Research; Cellular Biology
TGF-beta; EMT; Dab2; ILEI; hnRNP E1; Metastasis

Recommended Citations

Citations

  • Chaudhury, A. (2010). Transforming Growth Factor-Beta (TGFΒ)-Mediated Post-Transcriptional Regulation of Epithelial-Mesenchymal Transdifferentiation (EMT) [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1268963035

    APA Style (7th edition)

  • Chaudhury, Arindam. Transforming Growth Factor-Beta (TGFΒ)-Mediated Post-Transcriptional Regulation of Epithelial-Mesenchymal Transdifferentiation (EMT). 2010. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1268963035.

    MLA Style (8th edition)

  • Chaudhury, Arindam. "Transforming Growth Factor-Beta (TGFΒ)-Mediated Post-Transcriptional Regulation of Epithelial-Mesenchymal Transdifferentiation (EMT)." Doctoral dissertation, Cleveland State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=csu1268963035

    Chicago Manual of Style (17th edition)

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© 2010, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.