Abstract
The FoxO forkhead transcription factors FoxO4 (AFX), FoxO3a (FKHR.L1), and FoxO1a (FKHR) represent important physiological targets of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB) signaling. Overexpression or conditional activation of FoxO factors is able to antagonize many responses to constitutive PI3K/PKB activation including its effect on cellular proliferation. It was previously shown that the FoxO-induced cell cycle arrest is partially mediated by enhanced transcription and protein expression of the cyclin-dependent kinase inhibitor p27(kip1) (R. H. Medema, G. J. Kops, J. L. Bos, and B. M. Burgering, Nature 404:782-787, 2000). Here we have identified a p27(kip1)-independent mechanism that plays an important role in the antiproliferative effect of FoxO factors. Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb. Downregulation of D-type cyclins involves a transcriptional repression mechanism and does not require p27(kip1) function. Ectopic expression of cyclin D1 can partially overcome FoxO factor-induced cell cycle arrest, demonstrating that downregulation of D-type cyclins represents a physiologically relevant mechanism of FoxO-induced cell cycle inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Carcinoma
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Cell Cycle / physiology*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Colonic Neoplasms
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Cyclin D
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism
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Cyclins / genetics
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Cyclins / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Down-Regulation / physiology
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Enzyme Inhibitors / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Forkhead Transcription Factors
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Genes, Reporter
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Humans
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Hydroxytestosterones / pharmacology
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Mice
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Mice, Transgenic
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Phosphatidylinositol 3-Kinases / metabolism
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Promoter Regions, Genetic
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Protein Binding
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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Retroviridae / genetics
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Retroviridae / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin D
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Cyclins
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DNA-Binding Proteins
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Enzyme Inhibitors
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FOXO4 protein, human
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Forkhead Transcription Factors
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Hydroxytestosterones
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Proto-Oncogene Proteins
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Repressor Proteins
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Retinoblastoma Protein
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Transcription Factors
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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4,17 beta-dihydroxy-4-androstene-3-one
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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CDK4 protein, human
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Cdk4 protein, mouse
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases