title: Foxm1 mediates cross talk between Kras/mitogen-activated protein kinase and canonical Wnt pathways during development of respiratory epithelium.
abstract: While Kras/mitogen-activated protein kinase (MAPK) and canonical Wnt/β-catenin are critical for lung morphogenesis, mechanisms integrating these important signaling pathways during lung development are unknown. Herein, we demonstrate that the Foxm1 transcription factor is a key downstream target of activated Kras(G12D). Deletion of Foxm1 from respiratory epithelial cells during lung formation prevented structural abnormalities caused by activated Kras(G12D). Kras/Foxm1 signaling inhibited the activity of canonical Wnt signaling in the developing lung in vivo. Foxm1 decreased T-cell factor (TCF) transcriptional activity induced by activated β-catenin in vitro. Depletion of Foxm1 by short interfering RNA (siRNA) increased nuclear localization of β-catenin, increased expression of β-catenin target genes, and decreased mRNA and protein levels of the β-catenin inhibitor Axin2. Axin2 mRNA was reduced in distal lung epithelium of Foxm1-deficient mice. Foxm1 directly bound to and increased transcriptional activity of the Axin2 promoter region. Foxm1 is required for Kras signaling in distal lung epithelium and provides a mechanism integrating Kras and canonical Wnt/β-catenin signaling during lung development.
authors: Divisions of Pulmonary Biology, Perinatal Institute of the Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA. I-Ching.Wang@cchmc.org
authors: I-Ching
authors: IC
authors: Wang
authors: Jonathan
authors: J
authors: Snyder
authors: Yufang
authors: Y
authors: Zhang
authors: Julie
authors: J
authors: Lander
authors: Yuto
authors: Y
authors: Nakafuku
authors: James
authors: J
authors: Lin
authors: Gang
authors: G
authors: Chen
authors: Tanya V
authors: TV
authors: Kalin
authors: Jeffrey A
authors: JA
authors: Whitsett
authors: Vladimir V
authors: VV
authors: Kalinichenko
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D020928:Mitogen-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)