Abstract
To investigate the molecular basis of PTEN-mediated tumor suppression, we introduced a null mutation into the mouse Pten gene by homologous recombination in embryonic stem (ES) cells. Pten-/- ES cells exhibited an increased growth rate and proliferated even in the absence of serum. ES cells lacking PTEN function also displayed advanced entry into S phase. This accelerated G1/S transition was accompanied by down-regulation of p27(KIP1), a major inhibitor for G1 cyclin-dependent kinases. Inactivation of PTEN in ES cells and in embryonic fibroblasts resulted in elevated levels of phosphatidylinositol 3,4,5,-trisphosphate, a product of phosphatidylinositol 3 kinase. Consequently, PTEN deficiency led to dosage-dependent increases in phosphorylation and activation of Akt/protein kinase B, a well-characterized target of the phosphatidylinositol 3 kinase signaling pathway. Akt activation increased Bad phosphorylation and promoted Pten-/- cell survival. Our studies suggest that PTEN regulates the phosphatidylinositol 3,4, 5,-trisphosphate and Akt signaling pathway and consequently modulates two critical cellular processes: cell cycle progression and cell survival.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Cycle / physiology*
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Cell Cycle Proteins*
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Cell Division
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Cell Survival
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p27
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Embryo, Mammalian
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Genes, Tumor Suppressor*
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Genomic Library
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In Situ Nick-End Labeling
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Kinetics
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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PTEN Phosphohydrolase
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Phosphatidylinositol Phosphates / metabolism*
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Phosphoric Monoester Hydrolases / deficiency
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Phosphoric Monoester Hydrolases / genetics*
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Phosphoric Monoester Hydrolases / physiology
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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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Recombination, Genetic
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Restriction Mapping
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Signal Transduction
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Stem Cells / cytology
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Tumor Suppressor Proteins*
Substances
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Microtubule-Associated Proteins
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Phosphatidylinositol Phosphates
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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phosphatidylinositol 3,4,5-triphosphate
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Cyclin-Dependent Kinase Inhibitor p27
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase