Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D
| Autor: | Marc Schmidt, Rob Klompmaker, René H. Medema, Armando van der Horst, Boudewijn M.T. Burgering, Sylvia Fernandez de Mattos, Eric Lam, Geert J. P. L. Kops |
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| Jazyk: | angličtina |
| Rok vydání: | 2002 |
| Předmět: |
Transcription
Genetic Cyclin D Cell Cycle Proteins Retinoblastoma Protein Mice Phosphatidylinositol 3-Kinases Genes Reporter Enzyme Inhibitors Promoter Regions Genetic Cell Growth and Development Cells Cultured biology Cell Cycle Retinoblastoma protein FOXO Family Forkhead Transcription Factors 3T3 Cells Cyclin-Dependent Kinases Cell biology DNA-Binding Proteins Colonic Neoplasms biological phenomena cell phenomena and immunity Cyclin-Dependent Kinase Inhibitor p27 Protein Binding Down-Regulation Mice Transgenic Protein Serine-Threonine Kinases Geneeskunde Cyclin-dependent kinase Cyclins Proto-Oncogene Proteins Animals Humans Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cyclin-dependent kinase 4 Akt/PKB signaling pathway Tumor Suppressor Proteins fungi Carcinoma Cyclin-Dependent Kinase 4 Cell Biology Fibroblasts Repressor Proteins Retroviridae biology.protein Cancer research Hydroxytestosterones Proto-Oncogene Proteins c-akt Transcription Factors |
| Zdroj: | Molecular and cellular biology, 22(22), 7842. American society for microbiology |
| ISSN: | 0270-7306 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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