Abstract
In this study we report a new mechanism whereby cyclic AMP (cAMP) regulates the cell-cycle machinery. We demonstrate that elevation of intracellular levels of cAMP promotes degradation of cyclin D3 in proteasomes, and that this occurs via glycogen synthase kinase-3beta (GSK-3beta)-mediated phosphorylation of cyclin D3 at Thr-283. Elevation of cAMP did not change the subcellular distribution of either cyclin D3 or GSK-3beta. However, cAMP promoted the interaction between cyclin D3 and GSK-3beta both in vitro and in vivo, indicating that GSK-3beta-mediated phosphorylation of cyclin D3 might require the association between the two proteins. These results demonstrate how cAMP enhances degradation of cyclin D3. Furthermore, we provide evidence for a novel mechanism by which GSK-3beta might phosphorylate unprimed substrates in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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B-Lymphocytes / metabolism
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Blotting, Northern
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Cell Line
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Colforsin / pharmacology
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Cyclic AMP / metabolism*
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Cyclin D3
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Cyclins / metabolism*
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Dose-Response Relationship, Drug
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Genetic Vectors
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Glycogen Synthase Kinase 3 / metabolism*
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Glycogen Synthase Kinase 3 beta
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Humans
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Immunoprecipitation
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Lithium / pharmacology
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Microscopy, Fluorescence
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Phosphorylation
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Plasmids / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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RNA / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Subcellular Fractions
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Threonine / metabolism
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Time Factors
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Transfection
Substances
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CCND3 protein, human
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Cyclin D3
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Cyclins
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Recombinant Proteins
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Colforsin
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Threonine
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RNA
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Lithium
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Cyclic AMP
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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Proteasome Endopeptidase Complex