title: Inhibition of CDK2 promotes inducible regulatory T-cell differentiation through TGFβ-Smad3 signaling pathway.
abstract: Inducible regulatory T-cells (iTReg) can be generated from CD4(+)Foxp3(-) naïve conventional T-cells by a combination of TGF-β and T-cell receptor (TCR) signaling. It is of enormous clinical importance to identify agents that can promote the generation and differentiation of functional iTreg cells. We have established a phenotypic screening platform to identify new compounds that can promote the TGFβ-mediated iTreg differentiation. We have found Kenpaullone, a potent CDK1, CDK2 and CDK5 inhibitor, as new enhancer for iTreg cell differentiation. Kenpaullone promotes iTreg cell differentiation through increased and prolonged transcription of foxp3 gene by enhancing TGFβ-Smad3 signaling pathway. Thus, we have demonstrated that CDK2 is the biological target of Kenpaullone and proven that CDK2 is a novel negative regulator of iTreg cell differentiation.
authors: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
authors: Haijuan
authors: H
authors: Gu
authors: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
authors: Lixia
authors: L
authors: Ding
authors: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
authors: Si-Dong
authors: SD
authors: Xiong
authors: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China. Electronic address: xmgao@suda.edu.cn.
authors: Xiao-Ming
authors: XM
authors: Gao
authors: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bzheng@bcm.edu.
authors: Biao
authors: B
authors: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis; D001552:Benzazepines / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051900:Smad3 Protein / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D001552:Benzazepines; D007211:Indoles; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; C119620:kenpaullone; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; D016203:CDC2 Protein Kinase; C495893:Cdk2 protein, mouse; C495906:Cdk5 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3
keywords: Foxp3; Phenotypic screening; Regulatory T cells