Abstract
O‐GlcNAcylation of nuclear and cytoplasmic proteins is a major sensor of cellular nutrient status, and has extensive crosstalk with phosphorylation and other post‐translational modifications. This extensive crosstalk regulates transcription, signaling and cellular metabolism in response to nutrient status. O‐GlcNAcylation plays a fundamental role in gene transcription at many levels, including regulation of the basal machinery, as well as modifying the interactions and localizations of transcription factors. O‐GlcNAc is also part of the histone code. Prolonged excess O‐GlcNAcylation, as occurs in diabetes, underlies fundamental mechanisms of glucose toxicity. Abnormal O‐GlcNAcylation is associated with neurodegenerative disease, and is elevated in most types of cancer. Over one‐half of all kinases are both modified and many are regulated by O‐GlcNAcylation. O‐GlcNAcylation either inhibits or activates, depending upon the kinase, and can alter substrate specificity. Hyper‐O‐GlcNAcylation of mitochondrial proteins in diabetic tissues contributes directly to mitochondrial dysfunction. Mitochondrial O‐GlcNAc transferase (OGT) is strikingly elevated and mis‐localized in cardiac mitochondria from diabetic rats. O‐GlcNAcylation is very abundant at nerve terminals, where it is highly enriched on synaptic vesicle proteins, and appears to play a direct role in learning and memory. Focused, inducible knock out of OGT in adult brain neurons produces a satiety defect and a morbidly obese mouse within only three weeks. Supported by NIH R01CA42486, R01DK61671; N01‐HV‐00240; P01HL107153 and the Patrick C. Walsh Prostate Cancer Research Fund. Dr. Hart receives a share of royalty received by the universityon sales of the CTD 110.6 antibody, which are managed by JHU
Published Version
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