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J Cell Sci. 2004 Aug 1;117(Pt 17):3769-83. Epub 2004 Jul 13.

cAMP-induced degradation of cyclin D3 through association with GSK-3beta.

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Department of Medical Biochemistry, University of Oslo, P.O. Box 1112 Blindern, Oslo, N-0317, Norway.


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.

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