title: p27(Kip1) is important in modulating pulmonary artery smooth muscle cell proliferation.
abstract: Vascular remodeling due to pulmonary arterial smooth muscle cell (PASMC) proliferation is central to the development of pulmonary hypertension. Cell proliferation requires the coordinated interaction of cyclins and cyclin-dependent kinases (cdk) to drive cells through the cell cycle. Cdk inhibitors can bind cyclin-cdk complexes and cause G(1) arrest. To determine the importance of the cdk inhibitor p27(Kip1) in PASMC proliferation we studied [(3)H]thymidine incorporation, changes in cell cycle, cell proliferation, and protein expression of p27(Kip1) following serum stimulation in early passage rat PASMC. p27(Kip1) expression decreased to 40% of baseline after serum stimulation, which was associated with an increase in both [(3)H]thymidine incorporation and the percent of cells in S phase. p27(Kip1) binding to cyclin E decreased at 24 h, and this correlated with an increase in phosphorylation of retinoblastoma both in vivo and in vitro. Overexpression of p27(Kip1) decreased [(3)H]thymidine incorporation and reduced cell counts at 5 d compared with controls. PASMC obtained from p27(Kip1-/-) mice showed a 2-fold increase in [(3)H]thymidine incorporation (at 24 h) and cell proliferation compared with p27(Kip1+/+) PASMC when cultured in 10% fetal bovine serum (FBS). These results suggest an important role for p27(Kip1) in regulating PASMC mitogenesis and proliferation.
authors.affiliation: Center for Genetic Lung Disease and Division of Pulmonary Sciences and Critical Care Medicine, Department of Biochemistry, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. brian.fouty@uchsc.edu
authors.forename: B W
authors.initials: BW
authors.lastname: Fouty
authors.forename: B
authors.initials: B
authors.lastname: Grimison
authors.forename: K A
authors.initials: KA
authors.lastname: Fagan
authors.forename: T D
authors.initials: TD
authors.lastname: Le Cras
authors.forename: J W
authors.initials: JW
authors.lastname: Harral
authors.forename: M
authors.initials: M
authors.lastname: Hoedt-Miller
authors.forename: R A
authors.initials: RA
authors.lastname: Sclafani
authors.forename: D M
authors.initials: DM
authors.lastname: Rodman
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005434:Flow Cytometry; D015870:Gene Expression / Q000502:physiology; D006973:Hypertension / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology; D016296:Mutagenesis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013936:Thymidine / Q000493:pharmacokinetics; D014316:Tritium; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019927:Cyclin E; D025521:Tumor Suppressor Proteins; D014316:Tritium; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D013936:Thymidine