cAMP-induced degradation of cyclin D3 through association with GSK-3beta.
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.
Naderi
Soheil
S
Department of Medical Biochemistry, University of Oslo, P.O. Box 1112 Blindern, Oslo, N-0317, Norway.
Gutzkow
Kristine B
KB
Låhne
Hege U
HU
Lefdal
Siri
S
Ryves
W Johnathan
WJ
Harwood
Adrian J
AJ
Blomhoff
Heidi K
HK
D001402:B-Lymphocytes / Q000378:metabolism; D015152:Blotting, Northern; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D008094:Lithium / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013347:Subcellular Fractions; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
C534696:CCND3 protein, human; D056743:Cyclin D3; D016213:Cyclins; D011994:Recombinant Proteins; D005576:Colforsin; D013912:Threonine; D012313:RNA; D008094:Lithium; D000242:Cyclic AMP; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex