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TRANSCRIPTIONAL REGULATION of Hur in RENAL STRESS TRANSCRIPTIONAL REGULATION OF HuR IN RENAL STRESS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Sudha Suman Govindaraju Graduate Program in Biochemistry The Ohio State University 2014 Dissertation Committee: Dr. Beth S. Lee, Ph.D., Advisor Dr. Kathleen Boris-Lawrie, Ph.D. Dr. Sissy M. Jhiang, Ph.D. Dr. Arthur R. Strauch, Ph.D Abstract HuR is a ubiquitously expressed RNA-binding protein that affects the post- transcriptional life of thousands of cellular mRNAs by regulating transcript stability and translation. HuR can post-transcriptionally regulate gene expression and modulate cellular responses to stress, differentiation, proliferation, apoptosis, senescence, inflammation, and the immune response. It is an important mediator of survival during cellular stress, but when inappropriately expressed, can promote oncogenic transformation. Not surprisingly, the expression of HuR itself is tightly regulated at multiple transcriptional and post-transcriptional levels. Previous studies demonstrated the existence of two alternate HuR transcripts that differ in their 5’ untranslated regions and have markedly different translatabilities. These forms were also found to be reciprocally expressed following cellular stress in kidney proximal tubule cell lines, and the shorter, more readily translatable variant was shown to be regulated by Smad 1/5/8 pathway and bone morphogenetic protein-7 (BMP-7) signaling. In this study, the factors that promote transcription of the longer alternate form were identified. NF-κB was shown to be important for expression of the long HuR mRNA, as was a newly identified region with potential for binding the Sp/KLF families of transcription factors. Sp1-like factors were not found to regulate HuR expression, revealing a possible KLF family member activity in regulation of the long isoform. Further ii analysis revealed that at least seven potential KLF family members are expressed in LLC-PK1 cells. One of these, Krüppel-like factor 8 (KLF8), had previously been shown to have key roles in cell proliferation, survival, and invasiveness, like HuR. Chromatin immunoprecipitation confirmed binding of KLF8 to the putative Sp/KLF binding site under both normal and stressed conditions in LLC-PK1 cells, and overexpression of KLF8 increased HuR mRNA levels. Further, cellular stress induced by thapsigargin treatment of cultured proximal tubule cells or ischemic injury of native rat kidney resulted in a rapid decrease of KLF8 levels that paralleled those of the long HuR mRNA variant. NF- κB protein levels transiently increased during a recovery phase similar to long form HuR mRNA, suggesting it might be one of the predominant transcription factors in regulating the long variant during recovery phase following injury or stress. These results demonstrate that KLF family members, including KLF8, can participate in regulating expression of alternate forms of HuR mRNA along with NF-κB and Smad 1/5/8 under different cellular contexts. The differential expression of HuR mRNAs with alternate 5’ untranslated regions and translatabilities provides a mechanism for the stress-responsive regulation of HuR expression by two distinct pathways that include Smad 1/5/8 or KLF8 and NF-κB. iii Dedicated to my loving parents Govindaraju Gopala Krishna and Indira . iv Acknowledgments I would like to sincerely thank my advisor Dr. Beth Lee for providing me an opportunity to pursue my graduate study under her mentorship and guidance. Her mentoring over the years taught me perseverance, inculcated passion for research and also enabled me to graciously accept success and failure in science. She has been a constant source of support, motivation and enthusiasm at difficult times in my life and I cannot be more thankful for her unconditional support. My sincere thanks to committee members Dr. Kathleen Boris-Lawrie, Dr. Sissy Jhiang and Dr. Arthur Strauch for their valuable time, attention and excellent scientific guidance throughout my graduate career at The Ohio State University. I am greatly indebted to Dr.Margaret Nishikawara for her generous support and commitment to benefit graduate students of the Physiology and Cell Biology department. I would also like to thank the previous and current Chair persons of the Physiology and Cell Biology department in providing financial assistance to complete final stages of my dissertation project and Ms.Mary Treon for her excellent administrative support. I would also like to thank Dr.Periasamy, v Dr.Jhiang and Dr.Davis’s group members who made the deserted Hamilton hall basement corridors more human and lively and have extended their support over the years. I would also like to sincerely acknowledge Mr.Matt Misicka, Ms.Amy Kulesza and staff from the Center for Life Sciences Education on campus who hired me as a Graduate Teaching Assistant and provided an excellent infrastructure for me to grow as an instructor in teaching college level undergraduate biology and were committed to professional development for three long years of my doctoral training. I would like to thank current and previous lab members from the Lee lab, Dr.McMichael, Dr.Kotadiya, Dr.Jeyaraj Dr.Ayupova and Dr.Singh who all have been very helpful right from my initial days in the lab until project completion. I am also greatly indebted to my past advisor from Texas A&M university, Dr.Rafael Perez-Ballestero and co mentor Dr.Maribel Gonzalez-Garcia who have been instrumental in shaping my decision to pursue a research career. My journey would not have been successful without an awesome support group on whom I could lean on during difficult times. My gratitude and sincere thanks to my friends here at The Ohio State University- Tapasvi Lolla, Seetha Hariharan, Aishwarya Devaraj, Ramesh Venugopal, Aparna Lakshmanan, Gayathri Natarajan and Sai Kamarajugadda along with Pavan, Sowmitri and all of my Texas “family” whose continuous support and encouragement had helped me during entire course of graduate study. vi The list would not be complete without mentioning my gratitude to my family for their endless support and motivation- Parents Mr.Gopala Krishna and Mrs.Indira; to my brother and my sister-in-law, their angel Pratham, grandparents, my aunt Mrs.Subhadra and my dear cousin, friend Dr.Kishore Parsa and his wife Mrs.Suneeta Parsa who have been a constant source of support and inspiration. vii Vita June 1997…………………………………….Little Flower High School, Hyderabad, India. August 2001…………………………………..B.S. Physician Assistant, BITS-Pilani, India. August 2006………………………………..M.S. Biology& Biochemistry,Texas A&M University, USA. 2007 to present ………….……………………………….............Graduate Research Associate, The Ohio State University. Publications 1. Govindaraju S and Lee BS (2014). Kruppel like factor-8 is a stress responsive transcription factor that regulates expression of HuR. J Cell Physiol & Biochem (In Press). 2. Govindaraju S and Lee BS (2013). Adaptive and Maladaptive Expression of the mRNA Regulatory Protein HuR. World J of Biol Chem, 4, 111-118. 3. Singh M, Martinez AR, Govindaraju S and Lee BS (2013). HuR inhibits apoptosis by amplifying Akt signaling through a positive feedback loop. J Cell Physiol, 228, 182-9. viii 4. Pathi, SS., Jose, S., Govindaraju, S., Conde, JA., Romo, HE., Chamakura, KR., Claunch, CJ., Benito-Martín, A., Challa-Malladi, M., González- García, M., Ballestero RP (2012). zRICH, a protein induced during optic nerve regeneration in zebrafish, promotes neuritogenesis and interacts with tubulin. Brain Res, 1474, 29-39. 5. Jeyaraj, S.C., Singh, M., Ayupova, DA., Govindaraju S., Lee BS (2010). Transcriptional control of human antigen R by bone morphogenic protein. J Biol Chem, 285, 4432-40. Fields of Study Major Field: Biochemistry ix Table of Contents Abstract .................................................................................................................ii Dedication.............................................................................................................iv Acknowledgments ................................................................................................ v Vita ..................................................................................................................... viii Table of Contents ................................................................................................. x List of Tables ...................................................................................................... xiv List of Figures ......................................................................................................xv List of Abbreviations ......................................................................................... xviii Chapter 1: Introduction ..................................................................................... 1 1.1 Ischemia Reperfusion (IR) Injury .............................................................. 2 1.2 Gene Expression during and after Ischemia Reperfusion Injury ............. 5 1.3 RNA-binding Proteins in Kidney ............................................................... 8 1.4 Human Antigen-R (HuR) / Embryonic Lethal Abnormal Vision 1 (ELAV-1) .............................................................................................. 10 x 1.4.2 Expression of HuR during Development, Aging, and Cellular Senescence ............................................................................................. 11 1.4.3
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