Abstract
In the present study, we investigated the involvement of phosphatidylinositol 3-kinase (PI 3-kinase) activity in the progression of vascular smooth muscle cells (VSMCs) throughout the G1 phase of cell cycle. Addition of two selective inhibitors of PI 3-kinase, LY 294002 or wortmannin, to quiescent VSMCs prevented serum-induced DNA synthesis in a dose-dependent manner with IC50 of 8.7 +/- 2.0 microM and 53.9 +/- 8.5 nM, respectively. Time course studies revealed that the two PI 3-kinase inhibitors blocked VSMC proliferation in mid-late G1 phase, about 6 h before the G1/S transition. This G1 growth arrest was due, at least in part, to the reduction of the CDK2 associated kinase activity resulting mainly from the upregulation of the inhibitory protein p27KIP1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Animals
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Aorta / cytology
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CDC2-CDC28 Kinases*
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Cell Cycle Proteins*
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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 / metabolism*
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Dose-Response Relationship, Drug
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G1 Phase / drug effects*
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Microtubule-Associated Proteins / metabolism*
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Morpholines / pharmacology
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects*
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Serine-Threonine Kinases / metabolism*
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Swine
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Tumor Suppressor Proteins*
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Wortmannin
Substances
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Androstadienes
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Cell Cycle Proteins
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Chromones
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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 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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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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Wortmannin