title: Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27.
abstract: G1phase cell cycle proteins, such as cyclin-dependent kinase 6 (Cdk6) and its activating partners, the D-type cyclins, are important regulators of T-cell development and function. An F-box protein, called F-box only protein 7 (Fbxo7), acts as a cell cycle regulator by enhancing cyclin D-Cdk6 complex formation and stabilising levels of p27, a cyclin-dependent kinase inhibitor. We generated a murine model of reduced Fbxo7 expression to test its physiological role in multiple tissues and found that these mice displayed a pronounced thymic hypoplasia. Further analysis revealed that Fbxo7 differentially affected proliferation and apoptosis of thymocytes at various stages of differentiation in the thymus and also mature T-cell function and proliferation in the periphery. Paradoxically, Fbxo7-deficient immature thymocytes failed to undergo expansion in the thymus due to a lack of Cdk6 activity, while mature T cells showed enhanced proliferative capacity upon T-cell receptor engagement due to reduced p27 levels. Our studies reveal differential cell cycle regulation by Fbxo7 at different stages in T-cell development.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Shachi P
authors.initials: SP
authors.lastname: Patel
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Randle
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gibbs
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Cooke
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK. hl316@cam.ac.uk.
authors.forename: Heike
authors.initials: H
authors.lastname: Laman
mesh_terms: D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D051361:Cyclin-Dependent Kinase 6 / Q000276:immunology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000276:immunology*; D015536:Down-Regulation; D044783:F-Box Proteins / Q000235:genetics / Q000276:immunology*; D005260:Female; D017353:Gene Deletion; D008213:Lymphocyte Activation; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D044783:F-Box Proteins; C568633:FBXO7 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6
keywords: Cdk6; Cell cycle; Fbxo7; T-cell development; p27