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I IDENTIFICATION of a PHOSPHO IDENTIFICATION OF A PHOSPHO-HNRNP E1 NUCLEIC ACID CONSENSUS SEQUENCE MEDIATING EPITHELIAL TO MESENCHYMAL TRANSITION (138 PP.) Dissertation Advisor: Philip H. Howe Protein translational regulation by RNA binding proteins (RBPs) is a critical process in maintaining homeostasis. Epithelial to mesenchymal transition (EMT) is a process in which epithelial cells de-differentiate and become mesenchymal, increasing the propensity toward tumorigenesis and/or metastasis. We have identified a heterogeneous nuclear riboprotein E1 (hnRNP E1)-mediated post-transcriptional operon that controls transcript-selective translational regulation of epithelial / mesenchymal transition (EMT)-associated genes. In this regulatory mechanism, hnRNPE1 binds to the 3’-UTR of select transcripts and silences their translation. TGFβ reverses translational silencing through Akt2-dependent phosphorylation of hnRNP E1 at Ser-43, resulting in loss of hnRNP E1 binding to RNA. We have identified approximately forty pro-EMT / metastatic mRNAs that are regulated by this hnRNP E1 operon and our preliminary studies have revealed a short stretch of nucleic acids, that we have termed the BAT element (TGF-beta activated translational (BAT) element), present in their respective 3’-UTRs that may be responsible for hnRNP E1 binding. Herein, through the use of in-vitro and in-vivo assays, we demonstrate the contribution of BAT element mutations and constitutively high levels of pSer43 hnRNP E1 to cancer tumorigenesis and metastasis. i IDENTIFICATION OF A PHOSPHO-HNRNP E1 NUCLEIC ACID CONSENSUS SEQUENCE MEDIATING EPITHELIAL TO MESENCHYMAL TRANSITION A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Andrew S. Brown August 2015 © Copyright All rights reserved Except for previously published materials ii Dissertation written by Andrew S. Brown B.S., Youngstown State University, 2008 M.S., Youngstown State University, 2010 Ph.D., Kent State University, 2015 Approved by Philip H. Howe, Ph.D., Chairman, Department of Biochemistry, Doctoral Advisor Derek S. Damron, Ph.D., Professor, Department of Cellular and Molecular Biology Srinivasan Vijayaraghavan, Ph.D. Professor, Department of Cellular and Molecular Biology Olena Piontkivska, Ph.D., Associate Professor, Department of Biology Bidyut K. Mohanty, Ph.D., Assistant Professor, Department of Biochemistry Accepted by Ernest J. Freeman, Ph.D., Director, School of Biomedical Science James L. Blank, Ph.D., Dean, College of Arts and Sciences iii TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................ iv LIST OF FIGURES ..................................................................................................................... vi LIST OF TABLES ..................................................................................................................... viii ACKNOWLEDGEMENTS ......................................................................................................... x CHAPTER I .................................................................................................................................. 1 INTRODUCTION .................................................................................................................... 1 CHAPTER II ................................................................................................................................. 5 Computational Identification of Post Translational Modification Regulated RNA Binding Protein Motifs ............................................................................................................. 5 ABSTRACT ............................................................................................................................... 6 INTRODUCTION .................................................................................................................... 7 EXPERIMENTAL PROCEDURES ..................................................................................... 10 RESULTS ................................................................................................................................ 15 DISCUSSION .......................................................................................................................... 33 ACKNOWLEDGEMENTS ................................................................................................... 36 FUNDING ................................................................................................................................ 37 REFERENCES ........................................................................................................................ 38 CHAPTER III ............................................................................................................................. 42 Identification and Characterization of an hnRNP E1 Translational Silencing Motif ...... 42 iv ABSTRACT ............................................................................................................................. 43 INTRODUCTION .................................................................................................................. 44 EXPERIMENTAL PROCEDURES ..................................................................................... 48 RESULTS ................................................................................................................................ 53 DISCUSSION .......................................................................................................................... 77 ACKNOWLEDGMENTS ...................................................................................................... 80 FUNDING ................................................................................................................................ 81 REFERENCES ........................................................................................................................ 82 CHAPTER IV ............................................................................................................................. 86 Development of a Phosphorylated Serine 43 (hnRNP E1) Specific Antibody and Implications of Expression in Metastatic Cancer ................................................................ 86 ABSTRACT ............................................................................................................................. 87 INTRODUCTION .................................................................................................................. 88 EXPERIMENTAL PROCEDURES ..................................................................................... 93 RESULTS ................................................................................................................................ 96 DISCUSSION ........................................................................................................................ 110 ACKNOWLEDGEMENTS ................................................................................................. 112 FUNDING .............................................................................................................................. 113 REFERENCES ...................................................................................................................... 114 CHAPTER V ............................................................................................................................. 118 GENERAL SUMMARY ...................................................................................................... 118 REFERECES: ....................................................................................................................... 125 v LIST OF FIGURES Figure 1. Systems overview of RPTS Application Capabilities ............................................. 20 Figure 2. 3’-UTRs become divergent across evolution while conserving regulatory motifs. ....................................................................................................................................................... 24 Figure 3. RPTS predicted motif-containing genes interact with hnRNP E1. ....................... 27 Figure 4. Predicted motif-containing genes global set enrichment (GSEA) analysis. ......... 30 Supplementary Figure 1. Additional RBP motif training sets. .............................................. 32 Figure 5. Translational regulation of EMT-inducing genes is upregulated by TGFβ and knockout of hnRNP E1. .............................................................................................................. 55 Figure 6. EMT-inducing genes bind hnRNP E1 through their 3’UTR and are protected from exonuclease degradation. .................................................................................................. 59 Figure 7. hnRNP E1 binding nucleic acid motifs show a total loss of affinity for hnRNP E1 when in its phosphorylated state. .............................................................................................. 62 Figure 8. Unbiased exonuclease digestion of hnRNP E1 bound target mRNA allows for high-throughput analysis of protected RNA fragment sequences. ......................................... 65 Figure 9. Genomic exonuclease ION torrent analysis reveals 37 consensus motifs with conserved pyrimidine residues interspaced by variable structural regions. ......................... 68 Figure 10. Conservation of descriptor
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