Role for p27(Kip1) in Vascular Smooth Muscle Cell Migration.
BACKGROUND
Rapamycin is a potent inhibitor of smooth muscle cell (SMC) proliferation and migration. Rapamycin-mediated inhibition of SMC proliferation is associated with upregulation of the cyclin-dependent kinase inhibitor p27(Kip1). Previously, we showed that mixed embryonic fibroblasts obtained from p27(Kip1)(-/-) mice were relatively rapamycin-resistant, suggesting that p27(Kip1) plays an integral role in modulating the antiproliferative effects of rapamycin. We hypothesized that the antimigratory effect of rapamycin may also be mediated by p27(Kip1).


RESULTS
Rapamycin (1 to 10 nmol/L) inhibited basic fibroblast growth factor-induced migration of wild-type (WT) but not p27(Kip1)(-/-) SMCs in a dose-dependent manner (P<0.05) in a modified Boyden chamber. The effects of rapamycin on aortic SMC explant migration were also studied with WT, p27(+/-), and p27(-/-) mice. Rapamycin 4 mg. kg(-1). d(-1) IP for 5 days inhibited SMC migration by 90% in the WT and p27(Kip1)(+/-) (P<0.05) but not p27(Kip1)(-/-) animals.


CONCLUSIONS
Lack of p27(Kip1) reduces rapamycin-mediated inhibition of SMC migration. These novel findings suggest a role for p27(Kip1) in the signaling pathway(s) that regulates SMC migration.
Sun
J
J
Cardiology Division, Center for Molecular Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, Mount Sinai School of Medicine, New York, NY, USA.
Marx
S O
SO
Chen
H J
HJ
Poon
M
M
Marks
A R
AR
Rabbani
L E
LE
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001905:Botulinum Toxins; D042846:CDC2-CDC28 Kinases; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D018797:Cell Cycle Proteins; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D016222:Fibroblast Growth Factor 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D001905:Botulinum Toxins; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus; D016559:Tacrolimus