The University of Georgia Cancer Center is taking a broad-based and interdisciplinary approach to fighting cancer. Our areas of expertise are:
The University of Georgia Cancer Center is taking a broad-based and interdisciplinary approach to fighting cancer. Our areas of expertise are:
I have extensive experience with cell cycle regulation and signaling using mammalian tissue culture cells and C. elegans as experimental model systems. My background has provided a strong foundation in cell cycle regulation. As a graduate student with Dr. Jean Wang at UCSD, I studied the v-abl and c-abl tyrosine kinases and cell cycle regulation in mammalian tissue culture cells (a, b). As a postdoctoral fellow with Dr. Ed Hedgecock at Johns Hopkins University, I studied the regulation of cell proliferation in C. elegans. During my postdoctoral work, I co-discovered the cullin gene family when I cloned the cul-1 gene and showed that it was required for cell cycle exit in C. elegans (c). Cullins form the scaffold for cullin-RING ubiquitin ligase (CRL) complexes. A central focus of my laboratory is on the functions of CRL complexes, which we study in both C. elegans and mammalian tissue culture cells. CRLs are involved in diverse cellular pathways, and this has allowed us to make important discoveries in multiple areas of biology. We have discovered: how CRL4CDT2 complexes regulate DNA replication-licensing factors to ensure that genomic DNA is replicated only once per cell cycle; how CRL2FEM-1 controls sex determination by targeting the degradation of a Gli-family transcription factor; and how both CRL4 and CRL2 complexes regulate the cell cycle and cell motility by targeting the degradation of CDK-inhibitors (d). Current studies that focus on signaling include: the discovery that a CRL2 complex targets RSK1 and RSK2 for degradation in mammalian cells; the negative regulation of Notch signaling by the CRL2LRR-1 complex; and the discovery of a CRL-regulated pathway that links insulin signaling and the control of mitochondrial morphology. In an unrelated project, we created the first primary culture system for C. elegans germ cells and used it to identify a specific bacterial folate as an exogenous signal that stimulates germ stem cell proliferation. We show that the folate signaling occurs independently of the folate’s role as a vitamin in one-carbon metabolism, suggesting a new signaling pathway. This research has implications for cancer because the folate receptor is overexpressed in many cancer cells and promotes cancer proliferation. Our current research includes studies on non-canonical folate pathways in human cancer cells.
Georgia Research Alliance William Henry Terry, Sr. Eminent Scholar in Drug Discovery, and Professor of Biochemistry and Molecular Biology
We discovered O-GlcNAcylation (OGN) in the early 1980s. OGN is the cycling of N-acetylglucosamine on and off serine or threonine residues on nuclear and cytoplasmic proteins. OGN occurs on over four-thousand proteins where it serves as a nutrient sensor with extensive crosstalk with phosphorylation to regulate many cellular processes, including signaling, transcription, translation and mitochondrial functions. There is a rapidly growing literature suggesting that O-GlcNAcylation contributes to the properties and progression of cancer cells. O-GlcNAc cycling is universally elevated in cancer cells and, indeed, preventing increased O-GlcNAcylation can block cancer progression. Aberrant expression and activities of O-GlcNAc cycling enzymes, especially OGT, have been reported in all human cancers studied to date. Altered cellular metabolism is a major hallmark of cancer. Glucose uptake and glycolysis are accelerated in cancer cells (“Warburg Effect”), which gives cancer cells an advantage for intensive growth and proliferation. O-GlcNAc-dependent regulation of signaling pathways, transcription factors, enzymes, and epigenetic changes are all likely involved in metabolic reprograming of cancer. Several researchers have proposed that inhibition of hyper-O-GlcNAcylation could be a potential novel therapeutic target for cancer treatment. It has also been proposed that aberrant O-GlcNAcylated proteins might be novel biomarkers of cancer.
Currently, our laboratory is focused on the roles of OGN on -catenin in the functions of WNT signaling and in the epithelial-mesenchymal transition (EMT). In collaboration with Michael Pierce’s laboratory we are also investigating the roles of OGN in mechanisms of tumor cell suppression of the immune system.
I am interested in fatty acylation modification of proteins and its functional role in tumor progression. My early study demonstrated that protein palmitoylation is essential for the activity of Src family kinases. Gain of palmitoylation sites inhibits Src kinase activity, and loss of palmitoylation enhances Fyn kinase activity (Cai et al., PNAS, 2011). Since I joined UGA in 2013 as a tenure track faculty, my lab continuously focuses on how myristoylation and palmitoylation regulate Src family kinases, subsequently modulating their activity and oncogenic signaling. Thanks to the funding supports of the DOD and NIH, my lab investigated how dietary fatty acids regulates the activity of Src kinase and oncogenic potential. My lab has established experimental approaches of monitoring the biosynthesis of acyl-CoAs (Yang et al., Analytical Chemistry, 2017). We have clearly demonstrated that myristoylation is essential for Src mediated and high fat diet accelerated tumor progression. Myristoylation regulates the association of myristoylated Src in the cell membrane, its mediated kinase activity (Kim et al., JBC, 2017), and oncogenic signaling (Li et al., Neoplasia, 2018; Li et al., JBC, 2018). In addition, we have identified that a myristoyl-CoA analog, B13, and its derivatives could inhibit protein myristoylation and Src kinase activity (Kim et al., Cancer Research, 2017). Additionally, myristoylation is also essential for myristoylated proteins to be encapsulated into extracellular vesicles/exosomes. We extend our study to detect aggressive prostate tumors by monitoring myristoylated Src kinase in extracellular vesicles from blood plasma. We will potentially provide a non-invasive approach to detect the initiation of aggressive/metastatic tumors for the patients under active surveillance.
My research program is focused on deciphering the evolutionary rules governing the structure, function and regulation of complex cellular signaling systems, in particular protein kinases, using a combination of computational and experimental approaches. Important goals are to identify genomic variants associated with protein kinase regulation in disease and normal states and to develop computational resources for integrative mining of protein kinase data.
Unique qualifications: I am one among the very few investigators using a combination of computational and experimental approaches to investigate the evolution of regulation in the protein kinase fold-family of enzymes.
I have made impactful contributions describing the unique sequence and structural features of various protein kinase groups and families. My papers are well cited (over 2500 citations) and have provided a framework for understanding the complex modes of protein kinase regulation in diseases such as cancer. In recognition of my work, I have been invited to speak at major international meetings, serve on review panels, and co-organize international meetings on kinases. We have recently begun to study the evolution of glycosyltransferases and proteases using the specialized tools and resources developed for the study of protein kinases. I believe that that common evolutionary themes will emerge by studying these large enzyme super-families in parallel.
Collaborative team: As evidenced through my publications, I have a long and successful history of collaborative research with both domestic and international scholars. Collaborators include protein kinase biochemists, cell biologists and structural biologists. We have also collaborated with large-bioinformatics consortiums to develop new resources and annotations for the signaling community and are beginning to work with the glycobiology community to develop specialization tools for the study of glycoenzymes.
My laboratory identifies and characterizes O-linked glycans in a wide variety of contexts. My initial work concentrated on O-GlcNAc, in which I identified proteins bearing the modification, mapped sites of modification, and identified the enzyme that adds O-GlcNAc to proteins (OGT). In my own laboratory, I have focused on O-fucose and O-glucose glycans on Epidermal Growth Factor-like repeats (EGF repeats) and Thrombospondin Type 1 Repeats (TSRs). This research has contributed greatly to the identification and characterization of the unique enzymes required for synthesis of these glycans, including demonstrating that the Fringe family of Notch modulators are 3-N-acetylglucosaminyltransferases, molecular cloning, expression and characterization of POFUT1 and POFUT2, initial identification and characterization of the 3-glucosyltransferase modifying O-fucose on TSRs, demonstrating that the Notch-pathway gene Rumi encodes POGLUT1, and identifying the two xylosyltransferases responsible for elongating O-glucose. We recently identified two novel enzymes that add O-glucose to a novel site on EGF repeats: POGLUT2 and POGLUT2. We have all of these enzymes overexpressed and have used them to glycosylate EGF repeats and TSRs in vitro in sufficient quantities for structural studies (NMR and/or X-ray crystallography). In collaboration with others, we have recently solved the structure of three of these enzymes co-crystallized with their acceptor substrates: Rumi/POGLUT1 with an EGF repeat, XXYLT1 with and EGF-O-Glc-Xyl, and POFUT2 with a TSR. We have developed glycomic methods for analyzing O-fucose and O-glucose structures and glycoproteomic methods for site-specific O-glycan analysis on EGF repeats and TSRs. We mapped sites of glycosylation on mouse Notch1 and demonstrated which sites are necessary for Fringe enzymes to mediate their effects. We have also begun to use what we have learned about Notch glycosylation to develop inhibitors of Notch activity. In particular, we have demonstrated that fucose analogs can be used to inhibit Notch activity in a ligand-specific manner. This is the first example of a small-molecule inhibitor that functions in a ligand-specific manner.
I am a biomedical scientist specialized in translational research in urological cancers, prostate cancer (PCa) metastasis, tumor microenvironment and other lung diseases. My current research includes mechanisms regulating cellular plasticity in epithelial-to-mesenchymal transition (EMT), endothelial-barrier regulation and Endothelial-to-mesenchymal transition (EndMT) in PCa metastasis. The foundation for my research is built through several Intramural grants, Veteran’s affairs, American Heart, American Legion, NIH, and Department of defense, as Principal- or co-investigator. While my forte is laboratory research in experimental therapeutics, one of my major accomplishments has been the creation of a broad, multi-disciplinary research training program encompassing postdoctoral fellows, graduate and professional students, and residents that extend from the laboratory to the bedside. This training environment is significant as it educates people to be successful in the changing landscape of biomedical research. My trainees are able to move into their respected health care fields as practitioners and researchers with a firm mutual understanding of each other’s knowledge. I am also a NIH KL2 and TL1 core co-director representing UGA in the Research Education Executive Committee in its alliance with Emory, Georgia Tech, and Morehouse SOM that form the Georgia Clinical and Translational Science Alliance (Georgia-CTSA). This VA Merit review grant proposal seeks to identify and characterize the role of selected microRNAs in prostate cancer EMT and metastasis.
Ras oncoprotein activity is strongly influenced by post-translational modifications that occur at the COOH-terminus: isoprenylation, palmitoylation, proteolysis, and carboxylmethylation. Our studies are focused on the enzymes that direct these modifications and range from investigations of enzyme specificity to inhibitor development.
Dr. Fikri Avci is currently Associate Professor of Biochemistry and Molecular Biology at the Center for Molecular Medicine in the University of Georgia. Dr. Avci is a glycoimmunologist who has training in both chemistry and biology of complex carbohydrates. He received his Ph.D. in 2005 from Rensselaer Polytechnic Institute. Subsequently, he worked as a postdoctoral research associate (2006-2011) and a faculty member (2011-2013) in the Departments of Medicine and Microbiology and Immunobiology at Harvard Medical School. He currently runs an interdisciplinary research group at the interface of carbohydrate research and immunology with an objective to explore treatment of and protection from infectious diseases and cancers by understanding key molecular and cellular interactions between the components of the immune system and carbohydrate antigens associated with microbes or cancers.
Dr. J. Michael Pierce received his Ph.D. from the Johns Hopkins University Department of Biology, and he completed an NIH Postdoctoral Fellowship at the Univ. of California, Berkeley, Dept. of Biochemistry with Dr. Clinton Ballou. He was appointed an Assistant Professor in the Department of Cell Biology, Univ. of Miami Medical School in 1982, and received the 5-year Faculty Research Award from the American Cancer Society in 1988. After moving to the Univ. of Georgia in 1991, he has received the Distinguished Research Professor award, and serves as the endowed Mudter Professor of Cancer Research. He is also the Director of the University of Georgia Cancer Center and is Principal Investigator of the National Center for Biomedical Glycomics, an NCI U01 award focusing on cancer glycomarkers, as well as the NIGMS T32 Glycoscience Training Program for Graduate students, the only training program of its kind in the U.S. He is the Chair of the board of the non-profit East Georgia Cancer Coalition, which focuses on delivering cancer prevention and screening to underserved populations in eastern Georgia. His research focuses on the application of monoclonal antibody technologies to find glycoprotein targets for cancer therapies.
My laboratory is focused on understanding the role that post-translational modifications, specifically glycosylation, play in increasing functional diversity of proteins. For the last 16 years, my lab has primarily focused on the biomedical significance of O-glycosylation, specifically the nutrient-sensing O-GlcNAc modification of nuclear and cytosolic proteins and the O-mannosylation pathway that is defective in many cases of congenital muscular dystrophy. The laboratory also has extensive experience in analytical mass spectrometry and the development/application of glycomic and glycoproteomic capture, identification, and quantification approaches. I serve as a Co-Director of the ThermoFisher Scientific appointed center of excellence in glycoproteomics that allows my laboratory to interact at both the software and hardware level with a leading instrument manufacturer to drive technology developments like those outlined in this proposal.
Dr. Karumbaiah joined the University of Georgia’s Regenerative Bioscience Center and Animal Science Department in October 2013, where he is currently associate professor of regenerative medicine. His research is focused on the design and development of novel interventional therapies to combat traumatic brain injuries and invasive brain tumors. Dr. Karumbaiah received his PhD in 2007 from the University of Georgia. He subsequently joined Prof. Ravi Bellamkonda’s group in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine, where he designed and developed novel biomaterials for neural tissue repair. His research interests include (1) gaining a better understanding the brain tumor microenviroment in order to develop targeted therapies to stem tumor invasion and enhance the efficacy of standard-of-care therapeutics; and (2) the development of novel glycomaterial scaffolds and functional electrical stimulation tools to help trigger the endogenous regenerative cascade and facilitate functional recovery following traumatic insults to the nervous system. His laboratory has developed novel glycomaterials, microfluidic devices, and functional electrical stimulation tools to answer fundamental questions related to these areas of study. Dr. Karumbaiah has previously worked in product development and on new product launch projects at Monsanto Company, and served as study director for a medical device company. His research is funded by multi-year grants from the National Institutes of Health (NIH), National Science Foundation (NSF) Engineering Research Center for Cell Manufacturing Therapies (CMaT), the Alliance for Regenerative Rehabilitation Research and Training (AR3T), and seed-grants from the Regenerative Engineering and Medicine (REM) partnership.
My laboratory has invested over 15 years in developing tools to perform structural analysis of major and minor glycans isolated from small amounts of material. We have also recently been focused on high-throughput, semi-automated annotation of mass spectral data, an essential tool for expanding the scope of glycomic analysis to biomedical and basic research applications. With our developed techniques we have made major contributions to glycomics and glycoproteomics of normal and diseased tissues. We have also established the Drosophila melanogaster embryo as a premier model system for functional glycomics. We now possess a deeper understanding of the full complement of N-linked, O-linked, and glycosphingolipid glycans expressed in the Drosophila embryo than for any other organism. Our methods for structural analysis are mature and completely translatable to investigating the glycomes and glycoproteomes of any tissue or cell type. In addition, a major component of my independent career has focused on functional analysis of glycans in various organisms and cellular systems (Drosophila, mouse, pathogens, human leukocytes). I have successfully utilized forward and reverse genetics, molecular cloning, and cell-based screening approaches to identify and characterize glycan binding activities, glycan-based developmental phenotypes, and glycan processing mechanisms. These experiences, as well as the full range of my training in carbohydrate structure/function provide me with the necessary expertise to contribute meaningfully to the goals of this proposal.
We are interested in elucidating non-genetic drivers of cancer formation, progression and metastasis through computationally mining and modeling omic data of cancer tissues. We are particularly interested in understanding how pH related stress drives metabolic reprogramming and how new metabolic exits created for some of the reprogrammed metabolisms may causally link to various phenotypic behaviors of a cancer, such as cell proliferation, drug resistance and cell migration.