Abstract
The tumor suppressor PTEN is one of the most commonly inactivated genes in human cancer. Glioblastoma multiforme cells harboring mutant PTEN have abnormally high levels of 3' phosphoinositides and elevated protein kinase B activity. Expression of wild-type PTEN in glioma cells, containing endogenous mutant PTEN, reduces 3' phosphoinositides levels, inhibits PKB activity, and induces G1 cell cycle arrest. We investigated the mechanism of the PTEN-induced growth arrest in glioma cell lines. Expression of PTEN is associated with increased expression of p27Kip1, decreased expression of cyclins A and D3, inhibition of cdk2 activity, and dephosphorylation of pRb. Inactivation of p53, by the human papilloma virus E6 oncoprotein, does not prevent PTEN-induced G1 arrest, implying that p53 is not required for G1 arrest. In contrast, p27Kip1 antisense oligonucleotides abrogated the growth arrest induced by PTEN. Furthermore, blocking p27Kip1 expression prevented the PTEN-induced reduction of cyclin-dependent kinase 2 activity, indicating that p27Kip1 functions upstream of cyclin-dependent kinase 2 in the PTEN regulatory cascade. These results implicate p27Kip1 as a critical mediator of PTEN-induced G1 arrest.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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CDC2-CDC28 Kinases*
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / physiology
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Cell Division / physiology
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Chromones / pharmacology
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / physiology
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Enzyme Inhibitors / pharmacology
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G1 Phase / physiology*
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Glioma / pathology
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Humans
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / physiology*
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Morpholines / pharmacology
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PTEN Phosphohydrolase
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology*
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Protein Serine-Threonine Kinases / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / physiology
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Tumor Suppressor Proteins*
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Up-Regulation / physiology
Substances
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Cell Cycle Proteins
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Chromones
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Enzyme Inhibitors
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Microtubule-Associated Proteins
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human