Recently, a myriad of key nuclear and cytoskeletal proteins have been found to be dynamically modified by the attachment of single N- acetylglucosamine residues to hydroxyl groups of Serine or Threonine (termed, O-GlcNAc). O-GlcNAcylation is as abundant and as dynamic as is protein phosphorylation, and occurs in virtually all eukaryotes. In addition, O-GlcNAcylation appears to be reciprocal with protein O- phosphorylation on many proteins. Among proteins that are multiply O- GlcNAcylated are the major nuclear oncogenes, steroid receptors and tumor suppressors. The location of the O-GlcNAc moieties on these proteins suggest that the saccharide modification may play a key role in the molecular etiology of cancer. The goal of these studies is to elucidate the molecular functions and roles of the O-GlcNAcylation of the c-Myc oncogene protein, the retinoblastoma-related p107 tumor suppressor protein, protein kinase CKII and the estrogen receptor. The roles of O-GlcNAc in regulating the phosphorylation, subunit associations and transactivation activities of these molecules will be systematically investigated.
Specific Aims Are: 1) To Systematically Elucidate the Functions of O- GlcNAc on the c-Myc Oncogene Protein. 2) To Elucidate the Functional Relationships of O-GlcNAc and O- Phosphate on Rb Tumor Suppressors. 3) To Elucidate the Dynamic Relationship and Functions of O-GlcNAc and Phosphate on Protein Kinase CK2. 4) To Continue to Elucidate the Roles of O-GlcNAcylation of the Estrogen Receptor. Each of these aims are focusing on proteins key to the molecular etiology of cancer and cell growth regulation. The approach involves overlapping techniques in different biological systems to provide synergy in our efforts. These studies will provide an unexpected avenue for the development of chemotherapeutic agents that affect the O-GlcNAcylation state of these proteins. It is our hypothesis that O-GlcNAc plays a key role in the interplay of oncogene proteins with tumor suppressor gene products. Furthermore, the saccharide appears to modulate the transcriptional activities and cellular associations of key transcription factors involved in transformation to the oncogenic phenotype.
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