title: Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D.
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.
authors.affiliation: Division of Molecular Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmidt
authors.forename: Silvia
authors.initials: S
authors.lastname: Fernandez de Mattos
authors.forename: Armando
authors.initials: A
authors.lastname: van der Horst
authors.forename: Rob
authors.initials: R
authors.lastname: Klompmaker
authors.forename: Geert J P L
authors.initials: GJ
authors.lastname: Kops
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.forename: Boudewijn M T
authors.initials: BM
authors.lastname: Burgering
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002277:Carcinoma; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003110:Colonic Neoplasms; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051858:Forkhead Transcription Factors; D017930:Genes, Reporter; D006801:Humans; D006915:Hydroxytestosterones / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D051858:Forkhead Transcription Factors; D006915:Hydroxytestosterones; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C493961:Cdkn1b protein, mouse; C108803:FOXO4 protein, human; C032278:4,17 beta-dihydroxy-4-androstene-3-one; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse