Protein-Binding Function of RNA-Dependent Protein Kinase Promotes Proliferation through TRAF2/RIP1/NF-κB/c-Myc Pathway in Pancreatic β cells
| Autor: | DingYu Wang, XiaoQiang Qi, Jun Guo, ZhengZheng Ding, HuiWen Wu, LiLi Gao, Wei Tang |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Transcription
Genetic Cell Survival Catalysis Proto-Oncogene Proteins c-myc Mice eIF-2 Kinase Downregulation and upregulation Insulin-Secreting Cells Genetics Animals Humans Kinase activity Protein kinase A Molecular Biology Genetics (clinical) Cell Proliferation EIF-2 kinase biology Tumor Necrosis Factor-alpha GTPase-Activating Proteins NF-kappa B Articles TNF Receptor-Associated Factor 2 NFKB1 Protein kinase R Molecular biology Cell biology IκBα Gene Expression Regulation biology.protein Molecular Medicine Signal transduction Protein Binding Signal Transduction |
| Zdroj: | Molecular Medicine. 21:154-166 |
| ISSN: | 1528-3658 1076-1551 |
| DOI: | 10.2119/molmed.2014.00235 |
| Popis: | Double-stranded RNA-dependent protein kinase (PKR), an intracellular pathogen recognition receptor, is involved both in insulin resistance in peripheral tissues and in downregulation of pancreatic β-cell function in a kinase-dependent manner, indicating PKR as a core component in the progression of type 2 diabetes. PKR also acts as an adaptor protein via its protein-binding domain. Here, the PKR protein-binding function promoted β-cell proliferation without its kinase activity, which is associated with enhanced physical interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. In addition, the transcription of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-dependent survival gene c-Myc was upregulated significantly and is necessary for proliferation. Upregulation of the PKR protein-binding function induced the NF-κB pathway, as observed by dose-dependent degradation of IκBα, induced nuclear translocation of p65 and elevated NF-κB-dependent reporter gene expression. NF-κB-dependent reporter activity and β-cell proliferation both were suppressed by TRAF2-siRNA, but not by TRAF6-siRNA. TRAF2-siRNA blocked the ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1) induced by PKR protein binding. Furthermore, RIP1-siRNA inhibited β-cell proliferation. Proinflammatory cytokines (TNFα) and glucolipitoxicity also promoted the physical interaction of PKR with TRAF2. Collectively, these data indicate a pivotal role for PKR’s protein-binding function on the proliferation of pancreatic β cells through TRAF2/RIP1/NF-κB/c-Myc pathways. Therapeutic opportunities for type 2 diabetes may arise when its kinase catalytic function, but not its protein-binding function, is downregulated. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink