| First Author | Song Y | Year | 2015 |
| Journal | Mol Immunol | Volume | 68 |
| Issue | 2 Pt A | Pages | 341-9 |
| PubMed ID | 26446704 | Mgi Jnum | J:233870 |
| Mgi Id | MGI:5788238 | Doi | 10.1016/j.molimm.2015.09.007 |
| Citation | Song Y, et al. (2015) Activated PKR inhibits pancreatic beta-cell proliferation through sumoylation-dependent stabilization of P53. Mol Immunol 68(2 Pt A):341-9 |
| abstractText | Double-stranded RNA-dependent protein kinase (PKR) is intimately involved in type 2 diabetes due to its role in insulin resistance in peripheral tissues and anti-proliferative effect on pancreatic beta-cells. Activated PKR was found to inhibit beta-cell proliferation, partially through accumulation of P53. However the molecular mechanisms underlying PKR-dependent upregulation of P53 remain unknown. The results of the present study showed that PKR can be specifically activated in PKR overexpressing beta-cells by a low dosage of the previously synthesized compound 1H-benzimidazole1-ethanol,2,3-dihydro-2-imino-a-(phenoxymethyl)-3-(phenylmethyl)- ,monohydrochloride (BEPP), and this led to upregulation of P53 through sumoylation-dependent stability. Activated PKR was found to interact with sumo-conjugating enzyme Ubc9, and P53 sumoylation relies on a PKR-Ubc9 protein-protein interaction. Additionally, a ceramide signal was needed for PKR activation to be triggered by glucolipotoxicity and TNFalpha stimulation, and stabilization of P53 required endogenous ceramide accumulation. Glucolipotoxicity and pro-inflammatory cytokines therefore promote the sumoylation-dependent stability of P53 via the ceramide/PKR/Ubc9 signalling pathway that is involved in pancreatic beta-cell proliferation inhibition in the development of type 2 diabetes. |
