Abstract
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.
Highlights
Fbxo7 (F-box only protein 7) is a multi-functional protein with remarkable tissue-specific effects and is of clinical relevance in a variety of human pathologies, ranging from Parkinson’s disease and blood disorders to cancer [1,2,3]
In addition to this canonical function, Fbxo7 has other welldocumented SCF-independent roles, including acting as a cell cycle regulator in two ways: first, by interacting directly with the G1 phase kinase cyclin-dependent kinase 6 (Cdk6), promoting its binding activation by D-type cyclins, and second, by binding and stabilising the levels of cyclin-dependent kinase inhibitor (CDKI), p27 [1, 13, 14]. This cell cycle regulatory role of Fbxo7 is important in erythropoiesis, and we have reported that the reduction of Fbxo7 in a mouse causes anaemia, caused by a failure of differentiating erythroblasts to withdraw from the cell cycle due to insufficient levels of p27 [15, 16]
We demonstrate that Fbxo7 expression has opposing roles in cell proliferation within the T-cell lineage at different stages, promoting proliferation of thymocytes within the thymus, but restraining proliferation of activated T cells in the periphery
Summary
Fbxo (F-box only protein 7) is a multi-functional protein with remarkable tissue-specific effects and is of clinical relevance in a variety of human pathologies, ranging from Parkinson’s disease and blood disorders to cancer [1,2,3]. Substrates of SCFFbxo ligase include the kinetochore protein HURP, NF-jB signalling regulators c-IAP and TRAF2, and NRAGE, a protein involved in apoptosis arising from nerve growth factor signalling [9,10,11,12] In addition to this canonical function, Fbxo has other welldocumented SCF-independent roles, including acting as a cell cycle regulator in two ways: first, by interacting directly with the G1 phase kinase Cdk, promoting its binding activation by D-type cyclins, and second, by binding and stabilising the levels of cyclin-dependent kinase inhibitor (CDKI), p27 [1, 13, 14]. As neurons are post-mitotic, this is unlikely to involve its cell cycle regulatory activity
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