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2016 Scientific Report

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NING WU, PH.D. Dr. Wu received her Ph.D. from the Department of Biochemistry of the University of Toronto in 2002. She joined VARI in 2013 as an Assistant Professor. STAFF HOLLY DYKSTRA, B.S. ALTHEA WALDHART, B.S. STUDENT MATT HOLLOWELL RESEARCH INTERESTS Our laboratory studies the interface between cellular metabolism and signal transduction. The generation of two daughter cells depends on the proper uptake and use of nutrients that are often limited in the tumor environment. The distribution of these nutrients is controlled not only by the intrinsic catalytic rate and allosteric regulation of the enzymes, but also by post-translational modifications of these enzymes by signaling molecules. At the same time, signaling molecules must respond to cellular nutrient status and other cues such as environmental stresses and growth factors. Our laboratory focuses on key metabolic steps in glucose and lipid catabolism and aims to understand the mutual interactions between metabolites and signaling during cell replication. Fundamentally, cancer is a disease of uncontrolled cell growth. Relative to normal cells, tumor cells have aberrant metabolic addictions that differ depending on the cell’s tissue of origin and genetic mutations. By understanding the energy requirements and regulatory pathways of tumor cells, more-effective treatments can be developed. Our projects include unraveling the molecular mechanisms that regulate glucose uptake in cancers, investigating the effect of glucose on mitochondrial activity, and exploring the role of glucose as the link between metabolic syndrome and cancer incidence. 26 Van Andel Research Institute | Scientific Report

H. ERIC XU, PH.D. Dr. Xu went to Duke University and the University of Texas Southwestern Medical Center, earning his Ph.D. in molecular biology and biochemistry. He joined VARI in July 2002 and is now a Professor. Dr. Xu is also the Primary Investigator and Distinguished Director of the VARI–SIMM Research Center in Shanghai, China. STAFF XIANG GAO, PH.D. STEPHANIE GRANT, M.P.A. YUANZHENG (AJIAN) HE, PH.D. YANYONG KANG, PH.D. KUNTAL PAL, PH.D. KELLY POWELL, B.S. XIAOYIN (EDWARD) ZHOU, PH.D. STUDENTS ERIC LI HONGLEI MA, B.S. PARKER DE WAAL, B.S. TINGHAI XU, B.S. YAN YAN, B.S. YANTING YIN, B.S. FENG ZHANG, B.S. VISITING SCIENTISTS DAVID BENSON, PH.D. SOK KEAN KHOO, PH.D. ROSS REYNOLDS, PH.D. RESEARCH INTERESTS Hormone signaling is essential to eukaryotic life. Our research focuses on the signaling mechanisms of physiologically important hormones, striving to answer fundamental questions that have a broad impact on human health and disease. We are studying two families of proteins, the nuclear hormone receptors and the G protein–coupled receptors, because these proteins have fundamental roles in biology and are important drug targets for treating major human diseases. Nuclear hormone receptors The nuclear hormone receptors form a large family comprising ligand-regulated and DNA-binding transcription factors, which include receptors for the classic steroid hormones such as estrogen, androgens, and glucocorticoids, as well as receptors for peroxisome proliferator activators, vitamin D, vitamin A, and thyroid hormones. These receptors are among the most successful targets in the history of drug discovery: every receptor has one or more synthetic ligands being used as medicines. In the last five years, we have developed the following projects centering on the structural biology of nuclear receptors. Peroxisome proliferator–activated receptors The peroxisome proliferator–activated receptors (PPARα, β, and γ) are the key regulators of glucose and fatty acid homeostasis and, as such, are important therapeutic targets for treating cardiovascular disease, diabetes, and cancer. Millions of patients with type II diabetes have benefited from treatment with the novel PPARγ ligands rosiglitazone and pioglitazone. To understand the molecular basis of ligand-mediated signaling by PPARs, we have determined crystal structures of each PPAR’s ligand-binding domain (LBD) bound to many diverse ligands, including fatty acids, the lipid-lowering drugs called fibrates, and the new generation of anti-diabetic drugs, the glitazones. These structures have provided a framework for understanding the mechanisms of agonists CENTER FOR CANCER AND CELL BIOLOGY 27

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