Divisions of Pulmonary Biology, Perinatal Institute of the Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA.
Mol Cell Biol. 2012 Oct;32(19):3838-50. doi: 10.1128/MCB.00355-12. Epub 2012 Jul 23.
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.
虽然 Kras/丝裂原活化蛋白激酶（MAPK）和经典 Wnt/β-连环蛋白对于肺形态发生至关重要，但在肺发育过程中整合这些重要信号通路的机制尚不清楚。在此，我们证明 Foxm1 转录因子是激活的 Kras(G12D)的关键下游靶标。在肺形成过程中从呼吸上皮细胞中删除 Foxm1 可防止由激活的 Kras(G12D)引起的结构异常。Kras/Foxm1 信号在体内抑制了发育中的肺中经典 Wnt 信号的活性。Foxm1 在体外降低了激活的β-连环蛋白诱导的 T 细胞因子（TCF）转录活性。通过短发夹 RNA（siRNA）耗尽 Foxm1 增加了β-连环蛋白的核定位，增加了β-连环蛋白靶基因的表达，并降低了β-连环蛋白抑制剂 Axin2 的 mRNA 和蛋白水平。Foxm1 缺陷型小鼠的远端肺上皮中 Axin2 mRNA 减少。Foxm1 直接结合并增加 Axin2 启动子区域的转录活性。Foxm1 是远端肺上皮中 Kras 信号所必需的，并为肺发育过程中 Kras 和经典 Wnt/β-连环蛋白信号的整合提供了一种机制。
