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Ubiquitination and Sumoylation of Pregnane X Receptor UBIQUITINATION AND SUMOYLATION OF PREGNANE X RECEPTOR By Mengxi Sun Submitted to the graduate degree program in Pharmacology and Toxicology and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ________________________________ Chairperson Dr. Jeff Staudinger ________________________________ Dr. Rick Dobrowsky ________________________________ Dr. Alex Moise ________________________________ Dr. Honglian Shi ________________________________ Dr. Kristi Neufeld Date Defended: 1/8/2015 The Dissertation Committee for Mengxi Sun certifies that this is the approved version of the following dissertation: UBIQUITINATION AND SUMOYLATION OF PREGNANE X RECEPTOR ________________________________ Chairperson Dr. Jeff Staudinger Date approved: 1/8/2015 ii Abstract Pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor (NR) superfamily member expressed at high levels in the liver and intestine of mammals. PXR can be activated by a broad range of structurally diverse xenobiotics and endobiotics. As a key regulator of xenobiotic metabolism and clearance, activated PXR up-regulates the expression of genes encoding phase I (oxidation) and phase II (conjugation) metabolizing enzymes and phase III transporters to increase the metabolism and clearance of drugs and xenobiotics from the body, thus protecting the body from potential toxic insults. Besides xenobiotic metabolism and clearance, activation of PXR also involves in the regulation of many other important biochemical pathways, like inflammation and bile acid homeostasis. While ligand-binding is the primary mechanism for NRs activation, recent research indicates that post-translational modifications of NRs also help to determine their activities under different physiological conditions and represent new modes of regulation for NRs. Studies on post-translational modifications of PXR have just begun to emerge, how post-translational modifications regulate PXR activity is not well-understood. This dissertation focuses on ubiquitination and SUMOylation of PXR. These post-translational modifications of PXR were characterized and their effects on PXR activities were studied in both primary cultures of hepatocytes and immortalized cell lines. Data presented here indicate that PXR is a target of the ubiquitin proteasome system, and inhibition of proteasome activity decreases the transactivation of PXR. The E3s and SENPs (Sentrin-specific Protease) that regulate PXR SUMOylation and de-SUMOylation are identified. Utilizing the newly identified SENPs, SUMOylation is further confirmed to be indispensable for PXR iii to repress inflammatory response. Furthermore, the crosstalk between ubiquitination and SUMOylation at the level of PXR is explored. Our data indicate that SUMOylation increases the presence of ubiquitinated PXR, and many other substrates of ubiquitin. Taken together, this dissertation contributes to the understanding of post-translational modifications of PXR and their regulatory effects on drug metabolism and inflammation, which is expected to produce new opportunities for the development of novel and safe therapeutic strategies. iv Acknowledgements First and for most, I would like to thank my mentor, Dr. Jeff Staudinger for his advice and guidance throughout my graduate study. Without him, I would not be where I am today. I would also like to thank my dissertation committee of Dr. Rick Dobrowsky, Dr. Alex Moise, Dr. Honglian Shi, and Dr. Kristi Neufeld for their time, instruction, and support. I would like to thank all the faculty and staff in Department of Pharmacology and Toxicology, for the knowledge they taught me, the support they gave me, and also for the friendly environment they created. I would like to thank former and current members of the Staudinger lab, especially Dr. Chenshu Xu, Dr. Gang Hu, and Wenqi Cui for their instruction and help both in science and in life. I would like to thank all the former and current graduate students in Department of Pharmacology and Toxicology, for their support, understanding, and the lifelong friendship. I would like to thank my family for their unwavering support and encouragement over the years. I would also like to thank my friends for being there for me whenever I need them. I am so blessed to have them for their unconditional support and love. The research presented in this dissertation was funded by the National Institute of Digestive Diabetic and Kidney Diseases (R01DK090558) from the National Institutes of Health. v List of Abbreviations Aβ: Amyloid β-peptide ABCA1: ATP Binding Cassette Transporter A1 ACBP: Acyl-CoA Binding Protein AD: Alzheimer’s Disease AF-1: Activation Function 1 AF-2: Activation Function 2 AMP: Adenosine Monophosphate AMPK: AMP-activated Protein Kinase APL: Acute Promyelocytic Leukemia APP: Amyloid Precursor Protein AR: Androgen Receptor ATP: Adenosine Triphosphate BRCA1: Breast Cancer 1, Early Onset CAR: Constitutive Androstane Receptor vi CDK: Cyclin-dependent Kinase ChIP: Chromatin Immunoprecipitation CHIP: C-terminus of Hsc70 Interacting Protein CK: Caseine Kinase COX2: Cyclooxygenase 2 CPT1a: Carnitine Palmitoyltransferase 1A CRE: Cyclic AMP Response Element CREB: Cyclic AMP Response Element Binding Protein CYP: Cytochrome P450 DAX-1: Dosage-sensitive Sex Reversal, Adrenal Hypoplasia Critical Region, on Chromosome X, Gene 1 DBD: DNA-binding Domain DSS: Dextran Sulfate Sodium ER: Estrogen Receptor ERK: Extracellular Signal-regulated Protein Kinase FOXA2: Forkhead Box Transcription Factor A2 vii FOXO1: Forkhead Box Transcription Factor O1 FXR: Farnesoid X Receptor G6Pase: Glucose 6 Phosphatase GR: Glucocorticoid Receptor GRE: Glucocorticoid Response Element GSK3β: Glycogen Synthase Kinase 3β GST: Glutathione S Transferase HAT: Histone Acetyltransferase HDAC: Histone Deacetylase HGF: Hepatocyte Growth Factor HMGCS2: 3-Hydroxy-3-Methylglutarate-CoA Synthase 2 HNF4α: Hepatocyte Nuclear Factor 4 Alpha HRE: Hormone Response Element HSP: Heat Shock Protein IGP: Imidazoleglycerol Phosphate viii IL: Interleukin IL-1Ra: Interleukin 1 Receptor Antagonist JNK: C-jun N-terminal Kinase LBD: Ligand-binding Domain LCA: Lithocholic Acid LEF: Lymphoid Enhancer-binding Factor LPS: Lipopolysaccharide LRH-1: Liver Receptor Homolog 1 LXR: Liver X Receptor MAPK: Mitogen-activated Protein Kinase MDM2: Mouse Double Minute 2 Homolog MDR1: Multi-drug Resistance 1 MG132: N-Benzyloxycarbonyl- L-Leucyl-L-Leucyl-L-Leucinal MR: Mineralocorticoid Receptor MRP: Multi-drug Resistance Protein ix NCoR: Nuclear Receptor Co-repressor NF-κB: Nuclear Factor kappa-light-chain-enhancer of Activated B Cells NR: Nuclear Receptor Nurr1: Nuclear Receptor Related 1 Protein OAT1： Organic Anion Transporter 1 OATP2: Organic Anion Transporting Polypeptide 2 OATP1A2: Organic Anion Transporting Polypeptide 1A2 OCTN1：Organic Cation Transporter 1 PCN: Pregnenolone 16α-carbonitrile PEPCK: Phosphoenolpyruvate Carboxykinase PGC-1α: Peroxisome Proliferator Activated Receptor Gamma Co-activator 1 Alpha Pgp: P-glycoprotein PIAS: Protein Inhibitors of Activated STAT PIC: Pre-initiation Complexes PKA: Cyclic-AMP-dependent Protein Kinase x PPAR: Peroxisome Proliferator Activated Receptor PML: Promyelocytic Leukemia PR: Progesterone Receptor PTM: Post-translational Modification PXR: Pregnane X Receptor PXR-KO: Pregnane X Receptor Knockout RANBP2: Ran Binding Protein 2 RAR: Retinoic Acid Receptor RIF: Rifampicin RNF: RING Finger Protein ROR: RAR-related Orphan Receptor RXR: Retinoid X Receptor S14: Thyroid Hormone–responsive SPOT14 Homolog SAGA: Spt-Ada-Gcn5-acetyltransferase SCD-1: Stearoyl-CoA Desaturase-1 xi SDF-4: Stromal Cell Derived Factor 4 SENP: Sentrin-specific Protease SF-1: Steroidogenic Factor 1 SHP: Small Heterodimeric Partner SMRT: Silencing Mediator for Retinoid or Thyroid Hormone Receptors SRC: Steroid Receptor Coactivator STAT: Signal Transducers and Activators of Transcription SUG1: Suppressor for Gal1 SULT: Sulfotransferase SUMO: Small Ubiquitin-like Modifier TAF: TBP-associated Factor TBP: TATA-box Binding Protein TCF-4: T-cell Factor-4 TCPOBOP: 1, 4-bis [2-(3, 5-dichloropyridyloxy)] benzene TFIID: Transcription Factor-IID xii TLR: Toll-like Receptor TNFα: Tumor Necrosis Factor Alpha TR: Thyroid Receptor UGT: Uridine-5′-diphosphate Glucuronosyl Transferase VDR: Vitamin D Receptor VDRE: Vitamin D Response Element XREM: Xenobiotic Responsive Enhancer Module xiii Table of Contents Acceptance Page........................................................................................................................ ii Abstract..................................................................................................................................... iii Acknowledgements.....................................................................................................................v List of Abbreviations................................................................................................................ vi Table of Contents…................................................................................................................ xiv List of Tables.........................................................................................................................xviii List of Figures..........................................................................................................................xix Chapter 1: Introduction 1.1 Nuclear Receptors...............................................................................................................22
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