G protein-coupled receptor kinase 2(GRK2),as a key Ser/Thr protein kinase,belong to the member of the G protein-coupled receptor kinase(GRK)family.The C-terminus of GRK2 including a plekstrin homology domain and the N...G protein-coupled receptor kinase 2(GRK2),as a key Ser/Thr protein kinase,belong to the member of the G protein-coupled receptor kinase(GRK)family.The C-terminus of GRK2 including a plekstrin homology domain and the N-terminus of GRK2 including the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors(GPCRs),G protein,phospholipase C,phosphatidylinositol 4,5-bisphosphate,extracellular signal-regulated kinase,protein kinase A and Gβγ,which can regulate the activity of GRK2.GRK2 can regulate GPCR desensitization and internalization by phosphorylating the GPCR,promoting the affinity of binding to arrestins,and uncoupling the receptors from G proteins,which play an important role in maintaining the balance between the receptors and signal transduction.Previous studies have indicated that cardiac GRK2overexpression can promote the phosphorylation ofβ-adrenergic receptor(βAR)leading toβAR desensitization and internalization,which play a pivotal role in inducing heart failure(HF)-related dysfunction and myocyte death.GRK2,as a regulator of cell function,is overexpression in hypertension.Overexpression GRK2 can inhibit Akt/e NOS signaling pathway and decreased the production and activation of e NOS leading to endothelial dysfunction.Collagen-induced arthritis induces the upregulation of GRK2 expression in fibroblast-like synoviocytes.In this review,we mainly discussed the evidence for the association between GRK2 overexpression and various diseases,which suggests that GRK2 may be an effective drug target for preventing and treating heart failure,hypertension and inflammatory disease.展开更多
Neural cells undergo glutamate-induced apoptosis in ischaemic brain tissue,in which prostate apoptosis response-4 gene (Par-4)is involved.Human-bone mesenehymal stem cells can be utilized as an effective therapy for i...Neural cells undergo glutamate-induced apoptosis in ischaemic brain tissue,in which prostate apoptosis response-4 gene (Par-4)is involved.Human-bone mesenehymal stem cells can be utilized as an effective therapy for ischemic brain injury.In this study,we found that glutamate could induce apoptosis in human-bone mesenehymal stem cells,accompanied by increased expression of Par-4 gene and Smac release from mitochondria.Repressing Par-4 expression attenuated the glutamate-induced apoptosis.Both Par-4 protein and E2F1 protein could bind to E2F1-binding BS3 site on Smac promoter and participated in the formation of a pro- teins-DNA complex.Moreover,in the eomplex,E2F1,not Par-4,was found to be directly bound to the Smac promoter,suggesting that Par-4 exerted indireetly its transcriptional control on the Smac gene though interacting with E2F1.Expression of full-length Par-4 in human-bone mesenchymal cells resulted in increased activity of the Smac promoter.In addition,the indirect transcripional regula- tion of Par-4 on Smac depended on its COOH terminus-mediated interaction between Par-4 and E2F1.We conclude that the forma- tion of proteins-DNA complex,containing Par-4 protein,E2F1 protein and the Smac promoter,contributes to the pro-apoptotic effect on glutamate-treated human-bone mesenchymal stem cells.展开更多
基金supported by National Natural Science Foundation of China(8150212381330081)+1 种基金Natural Science Foundation of Anhui Province(1308085QH130)Provincial Natural Science Research Foundation of Anhui Province(KJ2014A119)
文摘G protein-coupled receptor kinase 2(GRK2),as a key Ser/Thr protein kinase,belong to the member of the G protein-coupled receptor kinase(GRK)family.The C-terminus of GRK2 including a plekstrin homology domain and the N-terminus of GRK2 including the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors(GPCRs),G protein,phospholipase C,phosphatidylinositol 4,5-bisphosphate,extracellular signal-regulated kinase,protein kinase A and Gβγ,which can regulate the activity of GRK2.GRK2 can regulate GPCR desensitization and internalization by phosphorylating the GPCR,promoting the affinity of binding to arrestins,and uncoupling the receptors from G proteins,which play an important role in maintaining the balance between the receptors and signal transduction.Previous studies have indicated that cardiac GRK2overexpression can promote the phosphorylation ofβ-adrenergic receptor(βAR)leading toβAR desensitization and internalization,which play a pivotal role in inducing heart failure(HF)-related dysfunction and myocyte death.GRK2,as a regulator of cell function,is overexpression in hypertension.Overexpression GRK2 can inhibit Akt/e NOS signaling pathway and decreased the production and activation of e NOS leading to endothelial dysfunction.Collagen-induced arthritis induces the upregulation of GRK2 expression in fibroblast-like synoviocytes.In this review,we mainly discussed the evidence for the association between GRK2 overexpression and various diseases,which suggests that GRK2 may be an effective drug target for preventing and treating heart failure,hypertension and inflammatory disease.
文摘Neural cells undergo glutamate-induced apoptosis in ischaemic brain tissue,in which prostate apoptosis response-4 gene (Par-4)is involved.Human-bone mesenehymal stem cells can be utilized as an effective therapy for ischemic brain injury.In this study,we found that glutamate could induce apoptosis in human-bone mesenehymal stem cells,accompanied by increased expression of Par-4 gene and Smac release from mitochondria.Repressing Par-4 expression attenuated the glutamate-induced apoptosis.Both Par-4 protein and E2F1 protein could bind to E2F1-binding BS3 site on Smac promoter and participated in the formation of a pro- teins-DNA complex.Moreover,in the eomplex,E2F1,not Par-4,was found to be directly bound to the Smac promoter,suggesting that Par-4 exerted indireetly its transcriptional control on the Smac gene though interacting with E2F1.Expression of full-length Par-4 in human-bone mesenchymal cells resulted in increased activity of the Smac promoter.In addition,the indirect transcripional regula- tion of Par-4 on Smac depended on its COOH terminus-mediated interaction between Par-4 and E2F1.We conclude that the forma- tion of proteins-DNA complex,containing Par-4 protein,E2F1 protein and the Smac promoter,contributes to the pro-apoptotic effect on glutamate-treated human-bone mesenchymal stem cells.
