title: Activated PKR inhibits pancreatic β-cell proliferation through sumoylation-dependent stabilization of P53.
abstract: 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 β-cells. Activated PKR was found to inhibit β-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 β-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 TNFα 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 β-cell proliferation inhibition in the development of type 2 diabetes.
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: XiaoMeng
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: LiLi
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: WeiPing
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China. Electronic address: hongwang6@sohu.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210029, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008156:Luciferases / Q000235:genetics / Q000276:immunology; D051379:Mice; D011485:Protein Binding; D055550:Protein Stability; D015398:Signal Transduction; D058207:Sumoylation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000276:immunology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000276:immunology*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D001562:Benzimidazoles; D002518:Ceramides; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D044763:Ubiquitin-Conjugating Enzymes; D019892:eIF-2 Kinase; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: Ceramide; P53; PKR; Pancreatic β-cell; Proliferation; Sumoylation