Protein OGlycosylation and Gene Expression

Because the major function of the HBP appears to be the generation of UDP-GlcNAc used for glycosylation, increasing numbers of studies have focused on this process. Whereas more complex glycosylation of secreted and extracellular domains of proteins appears to be regulated by enzymes localized to the endoplasmic reticulum and Golgi apparatus, the addition of a single O-GlcNAc moiety to protein Ser/Thr residues is catalyzed by uridine diphospho-N-acetyl-Glc:polypeptide P-N-acetylglucosaminyltrans-ferase (OGT) (EC 2.4.1.94). OGT is encoded by a single gene and resides largely in the nucleus. An alternatively spliced variant is localized to the mitochondria (43,44). Although the regulation of OGT is not completely understood, Hart has proposed that the intracellular levels of UDP-GlcNAc are limiting for intracellular protein O-glycosylation (9,11). For this reason, glucose concentration and activity of GFA are important determinants of overall levels of protein O-glycosylation. OGT targeting via protein-protein interactions likely imposes some substrate specificity under certain conditions (45). There is also one enzyme, O-GlcNAcase (O-P-N-acetylglucosaminidase EC 3.2.1.52 [hexosaminidase C]) which removes the O-GlcNAc moiety (46,47). This results in reversible alterations of protein function.

The protein targets of O-glycosylation are those primarily involved in transcriptional regulation, for example, RNA polymerase-associated proteins, transcription factors, and coactivators and corepressors (9-11). Several functional consequences of O-glycosylation have been documented such as increased DNA-binding (48), altered protein-protein binding (49,50), and decreased protein degradation (51). Depending on the cellular context, activation or repression of gene expression has been documented (52-55).

In the context of diabetic nephropathy, as outlined above, the expression of several genes; TGF-P1, laminin, fibronectin, and PAI-1 were stimulated by high glucose, Glc, and overexpression of GFA. Furthermore, inhibition of GFA blocked the effect of high glucose but not Glc (Fig. 3). These data support increased O-glycosylation secondary to HBP flux as playing a role.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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