title: Activation of double-stranded RNA-dependent protein kinase inhibits proliferation of pancreatic β-cells.
abstract: Double-stranded RNA-dependent protein kinase (PKR) is revealed to participate in the development of insulin resistance in peripheral tissues in type 2 diabetes (T2DM). Meanwhile, PKR is also characterized as a critical regulator of cell proliferation. To date, no study has focused on the impact of PKR on the proliferation of pancreatic β-cells. Here, we adopted insulinoma cell lines and mice islet β-cells to investigate: (1) the effects of glucolipotoxicity and pro-inflammatory cytokines on PKR activation; (2) the effects of PKR on proliferation of pancreatic β-cells and its underlying mechanisms; (3) the actions of PKR on pro-proliferative effects of IGF-I and its underlying pathway. Our results provided the first evidence that PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in pancreatic β-cells, and activated PKR significantly inhibited cell proliferation by arresting cell cycle at G1 phase. Reductions in cyclin D1 and D2 as well as increases in p27 and p53 were associated with the anti-proliferative effects of PKR, and proteasome-dependent degradation took part in the reduction of cyclin D1 and D2. Besides, PKR activation abrogated the pro-proliferative effects of IGF-I by activating JNK and disrupting IRS1/PI3K/Akt signaling pathway. These findings indicate that the anti-proliferative actions of PKR on pancreatic β-cells may contribute to the pathogenesis of T2DM.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, PR China; Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, PR China.
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, PR China; Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, PR China; Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Li-Ze
authors.initials: LZ
authors.lastname: Gu
authors.affiliation: Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, PR China.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Wu
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, PR China; Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, PR China. Electronic address: Guoj@njmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D056742:Cyclin D2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000633:toxicity; D018836:Inflammation Mediators / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008055:Lipids / Q000633:toxicity; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D056742:Cyclin D2; D016207:Cytokines; D018836:Inflammation Mediators; D008055:Lipids; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007334:Insulin-Like Growth Factor I; D019892:eIF-2 Kinase; D005947:Glucose
keywords: Diabetes; Glucolipitoxicity; PKR; Pancreatic β-cell; Pro-inflammatory cytokine; Proliferation