title: Increased expression of FoxM1 transcription factor in respiratory epithelium inhibits lung sacculation and causes Clara cell hyperplasia.
abstract: Foxm1 is a member of the Forkhead Box (Fox) family of transcription factors. Foxm1 (previously called Foxm1b, HFH-11B, Trident, Win, or MPP2) is expressed in multiple cell types and plays important roles in cellular proliferation, differentiation and tumorigenesis. Genetic deletion of Foxm1 from mouse respiratory epithelium during initial stages of lung development inhibits lung maturation and causes respiratory failure after birth. However, the role of Foxm1 during postnatal lung morphogenesis remains unknown. In the present study, Foxm1 expression was detected in epithelial cells of conducting and peripheral airways and changing dynamically with lung maturation. To discern the biological role of Foxm1 in the prenatal and postnatal lung, a novel transgenic mouse line that expresses a constitutively active form of FoxM1 (FoxM1 N-terminal deletion mutant or FoxM1-ΔN) under the control of lung epithelial-specific SPC promoter was produced. Expression of the FoxM1-ΔN transgene during embryogenesis caused epithelial hyperplasia, inhibited lung sacculation and expression of the type II epithelial marker, pro-SPC. Expression of FoxM1-ΔN mutant during the postnatal period did not influence alveologenesis but caused focal airway hyperplasia and increased proliferation of Clara cells. Likewise, expression of FoxM1-ΔN mutant in conducting airways with Scgb1a1 promoter was sufficient to induce Clara cell hyperplasia. Furthermore, FoxM1-ΔN cooperated with activated K-Ras to induce lung tumor growth in vivo. Increased activity of Foxm1 altered lung sacculation, induced proliferation in the respiratory epithelium and accelerated lung tumor growth, indicating that precise regulation of Foxm1 is critical for normal lung morphogenesis and development of lung cancer.
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of the Cincinnati Children's Hospital Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229, USA. I-Ching.Wang@cchmc.org
authors.forename: I-Ching
authors.initials: IC
authors.lastname: Wang
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Snyder
authors.forename: Mardi J
authors.initials: MJ
authors.lastname: Sutherland
authors.forename: Michael S
authors.initials: MS
authors.lastname: Burhans
authors.forename: John M
authors.initials: JM
authors.lastname: Shannon
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
mesh_terms: D000818:Animals; D049108:Cell Enlargement; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D011905:Genes, ras; D006801:Humans; D006965:Hyperplasia; D008168:Lung / Q000166:cytology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D020545:Respiratory Mucosa / Q000166:cytology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D050505:Mutant Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins
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