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PMID: 9832503 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.

Genes & development ·Vol. 12 ·No. 22 ·1998-11-15 ·Pages 3499-511

Diehl JA, Cheng M, Roussel MF, Sherr CJ

Abstract

The activities of cyclin D-dependent kinases serve to integrate extracellular signaling during G1 phase with the cell-cycle engine that regulates DNA replication and mitosis. Induction of D-type cyclins and their assembly into holoenzyme complexes depend on mitogen stimulation. Conversely, the fact that D-type cyclins are labile proteins guarantees that the subunit pool shrinks rapidly when cells are deprived of mitogens. Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1. Now, we demonstrate that glycogen synthase kinase-3beta (GSK-3beta) phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover. Because the activity of GSK-3beta can be inhibited by signaling through a pathway that sequentially involves Ras, phosphatidylinositol-3-OH kinase (PI3K), and protein kinase B (Akt), the turnover of cyclin D1, like its assembly, is also Ras dependent and, hence, mitogen regulated. In contrast, Ras mutants defective in PI3K signaling, or constitutively active mitogen-activated protein kinase-kinase (MEK1) mutants that act downstream of Ras to activate extracellular signal-regulated protein kinases (ERKs), cannot stabilize cyclin D1. In direct contrast to cyclin D1, which accumulates in the nucleus during G1 phase and exits into the cytoplasm during S phase, GSK-3beta is predominantly cytoplasmic during G1 phase, but a significant fraction enters the nucleus during S phase. A highly stable D1 mutant in which an alanine is substituted for the threonine at position 286 and that is refractory to phosphorylation by GSK-3beta remained in the nucleus throughout the cell cycle. Overexpression of an active, but not a kinase-defective, form of GSK-3beta in mouse fibroblasts caused a redistribution of cyclin D1 from the cell nucleus to the cytoplasm. Therefore, phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK-3beta.

MeSH Terms
3T3 Cells Animals Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Cycle/genetics Cyclins/metabolism Cysteine Endopeptidases/metabolism Fluorescent Antibody Technique Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Mice Multienzyme Complexes/metabolism Phosphorylation Phosphothreonine/analysis Proteasome Endopeptidase Complex Protein Binding/genetics
Chemicals
Cyclins Multienzyme Complexes Phosphothreonine Glycogen Synthase Kinases Calcium-Calmodulin-Dependent Protein Kinases Glycogen Synthase Kinase 3 Cysteine Endopeptidases Proteasome Endopeptidase Complex
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Diehl J A
Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 USA.
Cheng M
Roussel M F
Sherr C J
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.12.22.3499
Published
1998-11-15
Pages
3499-511
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC317244
Subset
IM
Grants
NCI NIH HHS · CA-21765 · United States
NCI NIH HHS · CA-56819 · United States
External Links
PubMed source DOI: 10.1101/gad.12.22.3499 PMC Full Text View journal details
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