title: Cdk5 controls IL-2 gene expression via repression of the mSin3a-HDAC complex.
abstract: Cyclin-dependent kinase 5 (Cdk5) is a unique member of a family of serine/threonine cyclin-dependent protein kinases. We previously demonstrated disruption of Cdk5 gene expression in mice impairs T-cell function and ameliorates T-cell-mediated neuroinflammation. Here, we show Cdk5 modulates gene expression during T-cell activation by impairing the repression of gene transcription by histone deacetylase 1 (HDAC1) through specific phosphorylation of the mSin3a protein at serine residue 861. Disruption of Cdk5 activity in T-cells enhances HDAC activity and binding of the HDAC1/mSin3a complex to the IL-2 promoter, leading to suppression of IL-2 gene expression. These data point to essential roles for Cdk5 in regulating gene expression in T-cells and transcriptional regulation by the co-repressor mSin3a.
authors.affiliation: a Department of Pediatrics; Division of Pediatric Hematology/Oncology; University Hospitals Rainbow Babies & Children's Hospital Center; The Angie Fowler Adolescent & Young Adult Cancer Institute; The Case Comprehensive Cancer Center ; Case Western Reserve University ; Cleveland , OH USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lam
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D007976:Leupeptins; D012333:RNA, Messenger; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D051360:Cyclin-Dependent Kinase 5; D056284:Histone Deacetylase 1; D056264:Sin3 Histone Deacetylase and Corepressor Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde