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PMID:10339565
| Citation |
Sun, H, Lesche, R, Li, DM, Liliental, J, Zhang, H, Gao, J, Gavrilova, N, Mueller, B, Liu, X and Wu, H (1999) PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc. Natl. Acad. Sci. U.S.A. 96:6199-204 |
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| 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. |
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| Keywords |
Animals; Cell Cycle/physiology; Cell Cycle Proteins; Cell Division; Cell Survival; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p27; Embryo, Mammalian; Genes, Tumor Suppressor; Genomic Library; In Situ Nick-End Labeling; Kinetics; Mice; Mice, Knockout; Microtubule-Associated Proteins/genetics; Microtubule-Associated Proteins/metabolism; PTEN Phosphohydrolase; Phosphatidylinositol Phosphates/metabolism; Phosphoric Monoester Hydrolases/deficiency; Phosphoric Monoester Hydrolases/genetics; Phosphoric Monoester Hydrolases/physiology; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-akt; Recombination, Genetic; Restriction Mapping; Signal Transduction; Stem Cells/cytology; Tumor Suppressor Proteins |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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