| First Author | Noordeen NA | Year | 2012 |
| Journal | Diabetes | Volume | 61 |
| Issue | 3 | Pages | 574-85 |
| PubMed ID | 22338092 | Mgi Jnum | J:196242 |
| Mgi Id | MGI:5487506 | Doi | 10.2337/db10-1329 |
| Citation | Noordeen NA, et al. (2012) Glucose-induced nuclear shuttling of ChREBP is mediated by sorcin and Ca(2+) ions in pancreatic beta-cells. Diabetes 61(3):574-85 |
| abstractText | Carbohydrate-responsive element-binding protein (ChREBP) is a regulator of pancreatic beta-cell gene expression and an important mediator of glucotoxicity. Glucose increases the activity and nuclear localization of ChREBP by still ill-defined mechanisms. Here we reveal, using both MIN6 and primary mouse beta-cells, a unique mechanism behind ChREBP nuclear translocation. At low glucose concentrations, ChREBP interacts with sorcin, a penta EF hand Ca(2+) binding protein, and is sequestered in the cytosol. Sorcin overexpression inhibits ChREBP nuclear accumulation at high glucose and reduced the activity of L-type pyruvate kinase (L-PK) and TxNIP promoters, two well-characterized ChREBP target genes. Sorcin inactivation by RNA interference increases ChREBP nuclear localization and in vivo binding to the L-PK promoter at low glucose concentrations. Ca(2+) influx was essential for this process since Ca(2+) chelation with EGTA, or pharmacological inhibition with diazoxide and nifedipine, blocked the effects of glucose. Conversely, mobilization of intracellular Ca(2+) with ATP caused the nuclear accumulation of ChREBP. Finally, sorcin silencing inhibited ATP-induced increases in intracellular Ca(2+) and glucose-stimulated insulin secretion. We therefore conclude that sorcin retains ChREBP in the cytosol at low glucose concentrations and may act as a Ca(2+) sensor for glucose-induced nuclear translocation and the activation of ChREBP-dependent genes. |
