Foxm1 mediates cross talk between Kras/mitogen-activated protein kinase and canonical Wnt pathways during development of respiratory epithelium

Mol Cell Biol. 2012 Oct;32(19):3838-50. doi: 10.1128/MCB.00355-12. Epub 2012 Jul 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein / genetics
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Deletion
  • Gene Expression Regulation, Developmental
  • Lung / abnormalities
  • Lung / embryology*
  • Lung / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Respiratory Mucosa / abnormalities
  • Respiratory Mucosa / embryology*
  • Respiratory Mucosa / metabolism
  • Transcriptional Activation
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway*
  • beta Catenin / analysis
  • beta Catenin / metabolism

Substances

  • Axin Protein
  • Axin2 protein, mouse
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxm1 protein, mouse
  • Wnt Proteins
  • beta Catenin
  • Mitogen-Activated Protein Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)