Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 25, Issue 5, Pages 652-658Publisher
AMER THORACIC SOC
DOI: 10.1165/ajrcmb.25.5.4592
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Funding
- NCI NIH HHS [R01 CA58187-085P50] Funding Source: Medline
- NHLBI NIH HHS [P01 HL 14985-29, R01 HL57282-03, HL48038-09] Funding Source: Medline
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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 ind cyclin-cdk complexes and cause G(1) arrest. To determine the importance of the cdk inhibitor p27(Kip1) in PASMC proliferation we studied [H-3]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 [H-3]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 [H-3]thymidine incorporation and reduced cell counts at 5 d compared with controls. PASMC obtained from p27(Kip1) mice showed a 2-fold increase in [H-3]thymidine incorporation (at 24 h) and cell proliferation compared with p27(Kip1+/+) PASMC when cultured in 10% fetal bovine serum (PBS). These results suggest an important role for p27(Kip1) in regulating PASMC mitogenesis and proliferation.
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