DeLamar Professor and Director of Biological Chemistry Johns Hopkins University School of Medicine
Dynamic O-GlcNAcylation of nuclear and cytosolic proteins.
Nuclear and cytoplasmic glycosylation. We recently described a major new form of protein glycosylation (termed O-GlcNAc) that is found in all multicellular organisms, including plants, animals and viruses that infect them. O-GlcNAc is ubiquitous, abundant and highly-dynamic, suggesting a regulatory role analogous to phosphorylation. O-GlcNAc is found on a myriad of nuclear and cytoplasmic proteins including chromatin proteins, RNA polymerase II and its transcription factors, oncogene proteins, heat shock proteins, nuclear pore proteins, viral proteins, and cytoskeletal proteins. A major thrust of our lab is to elucidate the biosynthesis, removal, attachments sites, and functions of this novel post-translational modification.
Glycosylation and cancer. Recently we found that many nuclear oncogenes, such as c-myc and adenovirus E1A or tumor suppressors are glycosylated by O-GlcNAc. Steroid receptors, such as the estrogen receptor are also glycosylated. O-GlcNAc appears to have a 'yin-yang' relationship with phosphorylation of these proteins. For example, c-myc is dynamically glycosylated on Thr-58, also a major site for GSK3 kinase action and the highest mutation 'hot-spot' in lymphomas. Much effort in the lab is directed at elucidating the roles these O-GlcNAc modifications in cancer. Glycosylation and neurobiology. Many of the proteins involved in synaptic transmission or cytoskeletal proteins important to nerve function and disease, such as glycosylated by O-GlcNAc. We are investigating the role of O-GlcNAc and its relation to phosphorylation of these proteins.
Nuclear glycosylation and diabetes. We are investigating the roles of nuclear and cytoplasmic glycosylation in mediating the toxicity of hyperglycemia and the role of transcription factor glycosylation in the control of the expression of the insulin gene. The O-GlcNAc transferase and O-GlcNAc-proteins are greatly enriched in the insulin-producing (-cells of the pancreas.