Phosphatidylinositol 3-kinase inhibitors block aortic smooth muscle cell proliferation in mid-late G1 phase: effect on cyclin-dependent kinase 2 and the inhibitory protein p27KIP1.
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.
Bacqueville
D
D
INSERM U 326, Toulouse, France.
Casagrande
F
F
Perret
B
B
Chap
H
H
Darbon
J M
JM
Breton-Douillon
M
M
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002867:Chromones / Q000494:pharmacology; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013552:Swine; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin
D000730:Androstadienes; D018797:Cell Cycle Proteins; D002867:Chromones; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000077191:Wortmannin