PTEN Induces Cell Cycle Arrest by Decreasing the Level and Nuclear Localization of Cyclin D1
| Autor: | Tsuyoshi Akagi, Aurelian Radu, Hidesaburo Hanafusa, Valerie Neubauer, Maria-Magdalena Georgescu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Cyclin E
Cyclin D Morpholines Cyclin A Cyclin B Active Transport Cell Nucleus Biology Protein Serine-Threonine Kinases Retinoblastoma Protein Glycogen Synthase Kinase 3 Phosphatidylinositol 3-Kinases Cyclin D1 Cyclin-dependent kinase Proto-Oncogene Proteins Phosphoprotein Phosphatases PTEN Humans Enzyme Inhibitors Phosphorylation Molecular Biology Cell Growth and Development Cells Cultured Phosphoinositide-3 Kinase Inhibitors Cell Nucleus Tumor Suppressor Proteins Cell Cycle PTEN Phosphohydrolase Cyclin-Dependent Kinase 4 Cell Biology Cyclin-Dependent Kinases Phosphoric Monoester Hydrolases Cell biology Chromones Mutation biology.protein Cancer research Lithium Chloride Proto-Oncogene Proteins c-akt Cyclin A2 Cell Division |
| Popis: | PTEN is a tumor suppressor frequently inactivated in brain, prostate, and uterine cancers that acts as a phosphatase on phosphatidylinositol-3,4,5-trisphosphate, antagonizing the activity of the phosphatidylinositol 3'-OH kinase. PTEN manifests its tumor suppressor function in most tumor cells by inducing G(1)-phase cell cycle arrest. To study the mechanism of cell cycle arrest, we established a tetracycline-inducible expression system for PTEN in cell lines lacking this gene. Expression of wild-type PTEN but not of mutant forms unable to dephosphorylate phosphoinositides reduced the expression of cyclin D1. Cyclin D1 reduction was accompanied by a marked decrease in endogenous retinoblastoma (Rb) protein phosphorylation on cyclin D/CDK4-specific sites, showing an early negative effect of PTEN on Rb inactivation. PTEN expression also prevented cyclin D1 from localizing to the nucleus during the G(1)- to S-phase cell cycle transition. The PTEN-induced localization defect and the cell growth arrest could be rescued by the expression of a nucleus-persistent mutant form of cyclin D1, indicating that an important effect of PTEN is at the level of nuclear availability of cyclin D1. Constitutively active Akt/PKB kinase counteracted the effect of PTEN on cyclin D1 translocation. The data are consistent with an oncogenesis model in which a lack of PTEN fuels the cell cycle by increasing the nuclear availability of cyclin D1 through the Akt/PKB pathway. |
| Databáze: | OpenAIRE |
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