title: Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition.
abstract: Alveolar epithelial cells (AECs) participate in the pathogenesis of pulmonary fibrosis, producing pro-inflammatory mediators and undergoing epithelial-to-mesenchymal transition (EMT). Herein, we demonstrated the critical role of Forkhead Box M1 (Foxm1) transcription factor in radiation-induced pulmonary fibrosis. Foxm1 was induced in AECs following lung irradiation. Transgenic expression of an activated Foxm1 transcript in AECs enhanced radiation-induced pneumonitis and pulmonary fibrosis, and increased the expression of IL-1β, Ccl2, Cxcl5, Snail1, Zeb1, Zeb2 and Foxf1. Conditional deletion of Foxm1 from respiratory epithelial cells decreased radiation-induced pulmonary fibrosis and prevented the increase in EMT-associated gene expression. siRNA-mediated inhibition of Foxm1 prevented TGF-β-induced EMT in vitro. Foxm1 bound to and increased promoter activity of the Snail1 gene, a critical transcriptional regulator of EMT. Expression of Snail1 restored TGF-β-induced loss of E-cadherin in Foxm1-deficient cells in vitro. Lineage-tracing studies demonstrated that Foxm1 increased EMT during radiation-induced pulmonary fibrosis in vivo. Foxm1 is required for radiation-induced pulmonary fibrosis by enhancing the expression of genes critical for lung inflammation and EMT.
authors.affiliation: Department of Pediatrics, Division of Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: David
authors.initials: D
authors.lastname: Balli
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ustiyan
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zhang
authors.forename: I-Ching
authors.initials: IC
authors.lastname: Wang
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Masino
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Ren
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
authors.forename: Tanya V
authors.initials: TV
authors.lastname: Kalin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics* / Q000502:physiology; D005355:Fibrosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors