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Title:
Nutrient Regulation of Signaling and Gene Expression by O-Linked N-AcetylGlucosamine
Abstract:
O-GlcNAcylation cycles on over nine thousand human nucleocytoplasmic and mitochondrial proteins, and it has extensive crosstalk with phosphorylation. O-GlcNAc is abundant on nearly all proteins involved in transcription, where it regulates gene expression in response to nutrients. For example, O-GlcNAc regulates the cycling of the TATA-binding (TBP) protein on DNA during the transcription cycle, and O-GlcNAc on RNA polymerase II is required for assembly of the pre-initiation complex. O-GlcNAc modifies at-least 34/80 ribosome proteins and many translation factors, and the sugar also regulates translation and mRNA selection. Targeted deletion of the O-GlcNAc Transferase (OGT) in excitatory neurons of adult mice results in a morbidly obese mouse with a satiety defect. Thus, O-GlcNAcylation not only serves as a nutrient sensor in all cells, but also directly regulates appetite. O-GlcNAcylation also regulates the trafficking of AMPA receptors in neurons and the development of functional synaptic spines. There are nearly two-thousand O-GlcNAcylated proteins at neuronal synapses. More than two-thirds of human protein kinases are O-GlcNAcylated and all kinases that have been tested are regulated by the sugar. Abnormal O-GlcNAcylation of CAMKII contributes directly to diabetic cardiomyopathy and to arrhythmias associated with diabetes. Prolonged elevation of O-GlcNAc, as occurs in diabetes, contributes directly to diabetic complications and is a major mechanism of glucose toxicity. Targeted over-expression of OGT to the heart causes severe heart failure in mice, which is reversed when they are crossed with mice having O-GlcNAcase over-expressed in their hearts. Drugs that elevate O-GlcNAcylation in the brain, which prevents hyperphosphorylation, appear to be of benefit for the treatment of Alzheimer’s and Parkinson’s disease in animal models. To date, all cancers have elevated O-GlcNAc cycling. Supported by NIH P01HL107153, R01GM116891, R01DK61671. Dr. Hart receives a share of royalty received on sales of the CTD 110.6 antibody, managed by JHU.
