title: Cyclin-dependent kinase 5 represses Foxp3 gene expression and Treg development through specific phosphorylation of Stat3 at Serine 727.
abstract: Cyclin-dependent kinase 5 (Cdk5) is known as a unique member of the cyclin-dependent family of serine/threonine kinases. Previously, we demonstrated Cdk5 to be an important regulator of T cell function and that disruption of Cdk5 expression ameliorates T cell mediated neuroinflammation. Here, we show a novel role of Cdk5 in the regulation of Foxp3 expression in murine CD4(+) T cells. Our data indicate that disruption of Cdk5 activity in T cells abrogates the IL-6 suppression of Foxp3 expression. This effect is achieved through Cdk5 phosphorylation of the signal transducer and activator of transcription 3 (Stat3) specifically at Serine 727 in T cells, and we show this post-translational modification is required for proper Stat3 DNA binding to the Foxp3 gene on the enhancer II region. Taken together, our data point to an essential role for Cdk5 in the differentiation of T cells as it regulates Foxp3 gene expression through phosphorylation of Stat3.
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies & Children's Hospital Center, The Angie Fowler Adolescent & Young Adult Cancer Institute, United States; The Case Comprehensive Cancer Center, Case Western Reserve University, United States; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Lam
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies & Children's Hospital Center, The Angie Fowler Adolescent & Young Adult Cancer Institute, United States; The Case Comprehensive Cancer Center, Case Western Reserve University, United States.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies & Children's Hospital Center, The Angie Fowler Adolescent & Young Adult Cancer Institute, United States; The Case Comprehensive Cancer Center, Case Western Reserve University, United States.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies & Children's Hospital Center, The Angie Fowler Adolescent & Young Adult Cancer Institute, United States; The Case Comprehensive Cancer Center, Case Western Reserve University, United States.
authors.forename: Byung-Gyu
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University Hospitals Rainbow Babies & Children's Hospital Center, The Angie Fowler Adolescent & Young Adult Cancer Institute, United States; The Case Comprehensive Cancer Center, Case Western Reserve University, United States; Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, United States. Electronic address: John.Letterio@uhhospitals.org.
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015850:Interleukin-6; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D051785:Smad Proteins; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D010768:Phosphoserine; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse
keywords: Cyclin dependent kinase; Phosphorylation; Post-translational; Regulatory T cell; Signaling