Perinatal Institute of the Cincinnati Childrens Hospital Research Foundation

Cincinnati, OH, United States

Perinatal Institute of the Cincinnati Childrens Hospital Research Foundation

Cincinnati, OH, United States

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Wang I.-C.,Perinatal Institute of the Cincinnati Childrens Hospital Research Foundation | Snyder J.,Perinatal Institute of the Cincinnati Childrens Hospital Research Foundation | Zhang Y.,Perinatal Institute of the Cincinnati Childrens Hospital Research Foundation | Lander J.,Perinatal Institute of the Cincinnati Childrens Hospital Research Foundation | And 6 more authors.
Molecular and Cellular Biology | Year: 2012

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 KrasG12D. Deletion of Foxm1 from respiratory epithelial cells during lung formation prevented structural abnormalities caused by activated KrasG12D. 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. © 2012, American Society for Microbiology.


PubMed | Perinatal Institute Of The Cincinnati Childrens Hospital Research Foundation
Type: Journal Article | Journal: Molecular and cellular biology | Year: 2012

While Kras/mitogen-activated protein kinase (MAPK) and canonical Wnt/-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 -catenin in vitro. Depletion of Foxm1 by short interfering RNA (siRNA) increased nuclear localization of -catenin, increased expression of -catenin target genes, and decreased mRNA and protein levels of the -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/-catenin signaling during lung development.

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