Abstract
The inhibitors of cyclin-dependent kinase (CDK) 4 (INK4) bind CDK4/6 to prevent their association with D-cyclins and G(1) cell cycle initiation and progression. We report here that among the seven CDK inhibitors, p18(INK4c) played an important role in modulating TCR-mediated T cell proliferation. Loss of p18(INK4c) in T cells led to hyperproliferation in response to CD3 stimulation. p18(INK4c)-null mice developed lymphoproliferative disorder and T cell lymphomas. Expression of IL-2, IL-2R-alpha, and the major G(1) cell cycle regulatory proteins was not altered in p18-null T cells. Both FK506 and rapamycin efficiently inhibited proliferation of p18-null T cells. In activated T cells, p18(INK4c) remained constant, and preferentially associated with and inhibited CDK6 but not CDK4. We propose that p18(INK4c) sets an inhibitory threshold in T cells and one function of CD28 costimulation is to counteract the p18(INK4c) inhibitory activity on CDK6-cyclin D complexes. The p18(INK4c) protein may provide a novel target to modulate T cell immunity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CD28 Antigens / immunology
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CD3 Complex / immunology
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CDC2-CDC28 Kinases*
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Cell Cycle
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Cell Cycle Proteins*
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Cell Division
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinase Inhibitor p18
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cytokines / biosynthesis
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Cytokines / metabolism
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Enzyme Inhibitors / pharmacology
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G1 Phase / drug effects
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Immunosuppressive Agents / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / physiology*
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Lymphoma, T-Cell / genetics
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Lymphoproliferative Disorders / genetics
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Mice
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Mice, Knockout
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Mice, SCID
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins*
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Receptors, Antigen, T-Cell / immunology*
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Sirolimus / pharmacology
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Tacrolimus / pharmacology
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
Substances
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CD28 Antigens
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CD3 Complex
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Cdkn2c protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p18
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Cytokines
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Enzyme Inhibitors
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Immunosuppressive Agents
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Proto-Oncogene Proteins
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Receptors, Antigen, T-Cell
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Tumor Suppressor Proteins
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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Cdk2 protein, mouse
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Cdk4 protein, mouse
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Cdk6 protein, mouse
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinases
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Sirolimus
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Tacrolimus