Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27.
Cellular and molecular life sciences : CMLS
MetadataShow full item record
Patel, S. P., Randle, S., Gibbs, S., Cooke, A., & Laman, H. (2017). Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27.. Cellular and molecular life sciences : CMLS, 74 1553-1566. https://doi.org/10.1007/s00018-016-2427-3
G₁ phase 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.
Thymus Gland, T-Lymphocytes, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Animals, Mice, Inbred C57BL, F-Box Proteins, Lymphocyte Activation, Cell Cycle, Apoptosis, Cell Differentiation, Cell Proliferation, Down-Regulation, Gene Deletion, Mutation, Female, Male, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase 6
This work was supported by the University of Cambridge, Department of Pathology Nina King studentship and the Biotechnology and Biological Sciences Research Council (BB/J007846/1), and the Cambridge Fund for the Prevention of Disease.
External DOI: https://doi.org/10.1007/s00018-016-2427-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262492
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International