| First Author | McGowan SE | Year | 2013 |
| Journal | Respir Res | Volume | 14 |
| Pages | 68 | PubMed ID | 23819440 |
| Mgi Jnum | J:199141 | Mgi Id | MGI:5500949 |
| Doi | 10.1186/1465-9921-14-68 | Citation | McGowan SE, et al. (2013) Platelet-derived growth factor-A regulates lung fibroblast S-phase entry through p27kip1 and FoxO3a. Respir Res 14:68 |
| abstractText | BACKGROUND: Secondary pulmonary alveolar septal formation requires platelet derived growth factor (PDGF-A) and platelet derived growth factor receptor-alpha (PDGFRalpha), and their regulation influences alveolar septal areal density and thickness. Insufficient PDGFRalpha expression in lung fibroblasts (LF) results in failed septation. METHODS: Mice in which the endogenous PDGFRalpha-gene regulates expression of the green fluorescent protein were used to temporally and spatially track PDGFRalpha-signaling. Transition from the G1/Go to the S-phase of the cell cycle was compared in PDGFRalpha-expressing and non-expressing LF using flow cytometry. Laser scanning confocal microscopy was used to quantify p27kip1 and forkhead box "other" 3a (FoxO3a) in the nuclei of alveolar cells from mice bearing the PDGFRalpha-GFP knock-in, and p27kip1 in mice with a conditional deletion of PDGFRalpha-gene function. The effects of PDGF-A on the phosphorylation and the intracellular location of FoxO3a were examined using Western immuoblotting and immunocytochemistry. RESULTS: In neonatal mouse lungs, entry of the PDGFRalpha-expressing LF subpopulation into the S-phase of the cell cycle diminished sooner than in their non-expressing LF counterparts. This preferential diminution was influenced by PDGFRalpha-mediated signaling, which phosphorylates and promotes cytoplasmic localization of FoxO3a. Comparative observations of LF at different ages during secondary septation and in mice that lack PDGFRalpha in alveolar LF demonstrated that nuclear localization of the G1 cyclin-dependent kinase inhibitor p27kip1 correlated with reduced LF entry into S-phase. CONCLUSIONS: Nuclear localization of FoxO3a, an important regulator of p27kip1 gene-expression, correlates with diminished proliferation of the PDGFRalpha-expressing LF subpopulation. These mechanisms for diminishing the effects of PDGFRalpha-mediated signaling likely regulate secondary septal formation and their derangement may contribute to imbalanced fibroblast cell kinetics in parenchymal lung diseases. |
