Abstract
Lymphocyte proliferation is key to the regulation of the immune system. Cyclin D2 is the first cell cycle protein induced following stimulation through the T-cell receptor, the B-cell receptor or cytokines. The promoter of this cyclin integrates a diverse range of signals. Through investigating the regulation of this promoter by interleukin-2 and phosphatidylinositol 3-kinase, we have identified a role for the transcription factor CREB, cAMP response element-binding protein. Mutation of the CREB-binding site reduced cyclin D2 promoter activity 5-10-fold. CREB-1 is phosphorylated at serine 133, a critical site for activity, in both T cells and Epstein-Barr virus immortalized B cells. The introduction of an S133A mutant of CREB-1 reduces IL-2 induction of cyclin D2 promoter activity, demonstrating a role for this phosphorylation site in promoter activity. Two inhibitors of protein kinase A reduce lymphocyte proliferation and CREB-1 phosphorylation. This study demonstrates that the cyclin D2 promoter is capable of being regulated by PI3K and CREB and identifies CREB-1 and protein kinase A as potential targets for altering lymphocyte proliferation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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B-Lymphocytes / drug effects*
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B-Lymphocytes / metabolism
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B-Lymphocytes / virology
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Blotting, Western
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Carbazoles / pharmacology
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Cell Proliferation / drug effects
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Cell Transformation, Viral
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / pharmacology*
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Cyclic AMP-Dependent Protein Kinases / pharmacology*
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Cyclin D2
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Cyclins / genetics
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Cyclins / metabolism*
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Electrophoretic Mobility Shift Assay
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Enzyme Inhibitors / pharmacology
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Humans
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Indoles / pharmacology
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Interleukin-2 / metabolism
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Isoquinolines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Promoter Regions, Genetic*
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Protein Kinase Inhibitors / pharmacology
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Pyrroles / pharmacology
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Sulfonamides / pharmacology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / metabolism
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Transcription, Genetic
Substances
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CCND2 protein, human
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Carbazoles
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Cyclic AMP Response Element-Binding Protein
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Cyclin D2
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Cyclins
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Enzyme Inhibitors
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Indoles
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Interleukin-2
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Isoquinolines
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Protein Kinase Inhibitors
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Pyrroles
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Sulfonamides
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KT 5720
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Phosphatidylinositol 3-Kinases
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Cyclic AMP-Dependent Protein Kinases
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N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide