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Thesis Written by Shorog Al Omair B.S., University of Dmmam, 2010 M.S

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Thesis Written by Shorog Al Omair B.S., University of Dmmam, 2010 M.S Thesis written by Shorog Al Omair B.S., University of Dmmam, 2010 M.S., Kent State University, 2015 Approved by Gail Fraizer, Associate Professor, Ph.D., Masters Advisor, School of Biomedical Sciences Ernest J. Freeman, Ph.D., Director, School of Biomedical Sciences James BlanK, Ph.D., Dean, College of Arts and Sciences Regulators of VEGF-a major isoforms in leukemia A thesis submitted To Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science by Shorog Al Omair July 2015 © Copyright All rights reserved Except for previously published materials TABLE OF CONTENTS TABLE OF CONTENTS………………………………………………………………………………….… iii LIST OF FIGURES……………………………………………………………………………...………….… iv LIST OF TABLES……………………………………………………………………………………………… v LIST OF ABBREVIATIONS…………………………………………………………………………….… vi ACKNOWLEDGMENTS………………….………………………………………………...………...….. viii I. INTRODUCTION…………………………………………………………………….………1 II. METHODOLOGY………………………………………………………….…………… 24 III. RESULTS…………………..………………………………………………………………29 IV. DISCUSSION……………...………………………………………………....….………..45 V. FUTURE DIRECTIONS……………......………………...………………..………….52 VI. REFERENCES……………...……………………………...………………..….…….….55 iii LIST OF FIGURES Figure 1. Alternative splicing regulatory sequences and splicing factors………......….7 Figure 2. The SR proteins shuttle between the cytoplasm and the nucleus……………12 Figure 3. WT1 structure.…………….….….……………………………………………………….....….14 Figure 4. Major VEGF-a isoforms.…………….….….…..……….………………....……………..….18 Figure 5. Characterization of VEGF-a major isoforms in K562 cells..............................32 Figure 6. WT1 inhibited VEGF121 without reducing VEGF165 in K562 cells……...…33 Figure 7. SRPK expression levels were not altered by WT1 transfection…………....34 Figure 8. SRPIN340 reduced VEGF-a isoforms in leuKemia cells…………………..……….37 Figure 9. SRPIN340 significantly reduced growth of U937 leuKemia cells ...............38 Figure 10. EGF up-regulated VEGF-a in K562 leuKemia cells…………………………...……40 Figure 11. SRPIN340 attenuated EGF-mediated induction of VEGF-a isoforms…..42 Figure 12. SRPIN340 reduces the nuclear intensity of SR proteins in K562………..44 Figure 13. Proposed model of EGF/SRPK1/SR pathway regulating VEGF isoform expression ………………………………………………………………………………………….54 iv LIST OF TABLES Table 1. WHO classification of hematopoietic tumors of non-lymphoid origin…….…..3 Table 2. WHO classification of tumors of lymphoid origin.…………..……………….…….…..4 Table 3. The nomenclature of the 12 SR splicing factors.……………………..……..........…….8 v LIST OF ABBREVIATIONS ALL Acute Lymphocytic LeuKemia AML Acute Myeloid LeuKemia AS Alternative Splicing CML Chronic Myeloid LeuKemia ClK/sty CDC-like kinase CLL Chronic Lymphocytic leuKemia ECM Extra Cellular Matrix EGF Epidermal Growth Factor EGFR Epidermal Growth Factor Receptor ESE Exonic splicing Enhancer ESS Exonic splicing suppressor hnRNPs Heterogeneous Nuclear Ribonucleoparticles ISE Intronic Splicing Enhancer ISS Intronic Splicing Suppressor vi MDS Myelodysplastic Syndrome NRPs Neuropilins snRNPs Small Nuclear Ribonucleoproteins SR Serine-Arginine-Rich SRPK Serine-Arginine Protein Kinases SRSF Serine-Arginine-Rich Splicing Factor RRMs RNA Recognition Motif VEGF-a Vascular Endothelial Growth Factor-a VEGFR Vascular Endothelial Growth Factor Receptor WHO World Health Organization vii ACKNOWLEGEMENT The completion of this thesis would not have been possible without the support of many peoples. First, I would liKe to express my deep appreciation and gratitude to my advisor, Dr. Gail Fraizer, for her continuous guidance, motivation, and support. I value everything I learned from her about all aspects of scientific research. Her advice, and editorial comments guided me through during the process of writing the thesis. I would like to thank my committee members, Dr. Gary KosKi, and Dr. Steven Kuerbitz for their time, advice, and suggestions that helped improve this work. I would also liKe to thanK all members of our lab for their cooperation and teamworK. I would liKe to thanK, Sony Pandey, for her mentoring, and contribution with experiments. The support of my family was essential for the successful completion of this worK. I would liKe to thanK my parents for believing in me, and raising me to thinK beyond social stereotypes. Finally, I would liKe to express my endless gratitude to my lovely husband, Abdulaziz, for his endless support, and encouragement during this challenging journey. viii CHAPTER 1 Introduction Overview of hematologic malignancies Blood cells are formed in the bone marrow in a physiological, developmental process called hematopoiesis. Irregularities in hematopoiesis lead to uncontrolled growth of a subset of blood cells resulting in leuKemia (Kumar, Abbas, & Aster, 2014). LeuKemia refers to a heterogeneous group of hematologic malignancies. LeuKemia is classified into chronic and acute leuKemia and further classified based on cell lineage into myeloid and lymphoid. There are four major four types of leuKemia: chronic myeloid leuKemia (CML), chronic lymphocytic leuKemia (CLL), acute myeloid leuKemia (AML), and acute lymphocytic leuKemia (ALL).(Jones, 2010) The cytogenetic translocations, or alterations, that are linked to the etiology of a subset of leuKemia, are commonly used to categorize that subset. One example is chronic myeloid leuKemia that is caused by the Philadelphia chromosome translocation (Bcr-abl t(9;22))(Jones, 2010). Lymphoma is another neoplastic disorder of lymphatic cells that originates in the lymphoid system. However, there is a fine line that separates lymphoma from leuKemia because it can disseminate into the bone marrow and present a leuKemia-like picture (Kumar et al., 2014). More detailed classifications of myeloid and lymphoid leuKemia are described in the 2008 1 World Health Organization (WHO) classification (Table.1 and 2)(Jones, 2010). Discoveries of molecular mechanisms contributing to leuKemia have helped in the advances in leuKemia therapeutic approaches and the increase in survival rate. (Kimura, Ando, & Kojima, 2014) However, more worK needs to be done to understand the underlying molecular mechanisms contributing to leuKemia. 2 Table.1 2008 WHO classification of hematopoietic tumors of nonlymphoid origin. adapted from (Jones, 2010) 3 Table.2 2008 WHO classification of tumors of lymphoid origin, adapted from (Jones, 2010). 4 Pre-mRNA splicing: The numbers of genes encoded in the human genome does not reflect the complexity and diversity of proteins expressed. One explanation for such diversity is the tightly regulated process of Alternative Splicing (AS)(Graveley, 2001). There are two types of pre-mRNA splicing, the regulated alternative pre-mRNA splicing and the constitutive pre-mRNA splicing (Black, 2003; Kornblihtt et al., 2013). The constitutive pre-mRNA splicing refers to the process where the transcript is always spliced the same way, liKe in the case of the splicing of introns, and the constitutive removal of certain exon(s). Alternative splicing is the process where exons can be alternatively spliced (either excluded or included) under different conditions allowing the differential expression of varying splice isoforms from the same gene. The mechanism of RNA splicing involves a biochemical reaction accomplished by large complex machinery called the spliceosome. The spliceosome is composed of small nuclear ribonucleoproteins (snRNPs) U1, U2, U4/U6 and U5; and non-small nuclear ribonucleoproteins (splicing factors) (BlacK, 2003; Krämer, 1996). Splicing factors recognize and bind specific sequences of the pre-mRNA that can either be enhancers of the spliceosome recognition of the splice site (Splicing Enhancer) or negative suppressor sequence (splicing Silencer) blocKing the spliceosome recognition of the splice site (Kornblihtt et al., 2013). These enhancer and suppressor sequences can be either intronic or exonic. Thereby splicing factors can bind intronic splicing enhancer (ISE), exonic splicing Enhancer (ESE), intronic splicing suppressor (ISS), or exonic splicing suppressor (ESS) (Figure1). 5 There are two major families of splicing factors, the serine- and arginine-rich protein family (SR splicing factors) and the hnRNPs proteins (heterogeneous nuclear ribonucleoparticles) (Figure2) (S. Lin & Fu, 2007; Martinez-Contreras et al., 2007; Zahler, Lane, Stolk, & Roth, 1992). The serine- and arginine-rich proteins (SR splicing factors) are RNA-binding proteins that have an amino terminus RNA recognition domain, and SR rich carboxyl terminus (Graveley, 2000; Krämer, 1996; Shepard & Hertel, 2009; Twyffels, Gueydan, & Kruys, 2011). SR proteins shuttle between the cytoplasm and the nucleus to function in constitutive and alternative splicing of pre-mRNA. Other functions of SR proteins have also been described, such as involvement in transcriptional elongation, mRNA export, mRNA stability and translational efficiency (Twyffels et al., 2011). The number of defined SR proteins is currently 12 (Table.3) and they have now been re-named for consistency (Manley & Krainer, 2010). 6 Figure 1. Alternative splicing regulatory sequences and splicing factors. Splicing factors (SR or hnRNP) bind intronic splicing enhancer (ISE), exonic splicing Enhancer (ESE), intronic splicing suppressor (ISS), or exonic splicing suppressor (ESS). When splicing factor binds an enhancer, this promotes the spliceosome recognition of the nearby splice site(s). Splicing factor binding to a suppressor sequence blocks the recognition of the nearby splice site and inhibits splicing. Adapted
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