4.6 Article

FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells

期刊

CELLS
卷 11, 期 7, 页码 -

出版社

MDPI
DOI: 10.3390/cells11071122

关键词

FOXO1-NKX2; 1 interaction; keratinocyte growth factor (KGF); PI-3K; AKT; alveolar epithelial cell; differentiation; transcription

资金

  1. Hastings Foundation
  2. American Cancer Society [RSG-20-135-01]
  3. Department of Defense [W81XWH-21-1-0231]
  4. National Institutes of Health [HL114959, R35HL135747, HL144932, HL122764, HL143059]

向作者/读者索取更多资源

NKX2.1 and FOXO1 have significant interactions in regulating specific gene expression and cell fate in the distal lung, with FOXO1 playing a central role in alveolar epithelial cell differentiation and maintaining homeostasis.
NKX2.1 is a master regulator of lung morphogenesis and cell specification; however, interactions of NKX2.1 with various transcription factors to regulate cell-specific gene expression and cell fate in the distal lung remain incompletely understood. FOXO1 is a key regulator of stem/progenitor cell maintenance/differentiation in several tissues but its role in the regulation of lung alveolar epithelial progenitor homeostasis has not been evaluated. We identified a novel role for FOXO1 in alveolar epithelial cell (AEC) differentiation that results in the removal of NKX2.1 from surfactant gene promoters and the subsequent loss of surfactant expression in alveolar epithelial type I-like (AT1-like) cells. We found that the FOXO1 forkhead domain potentiates a loss of surfactant gene expression through an interaction with the NKX2.1 homeodomain, disrupting NKX2.1 binding to the SFTPC promoter. In addition, blocking PI-3K/AKT signaling reduces phosphorylated FOXO-1 (p-FOXO1), allowing accumulated nuclear FOXO1 to interact with NKX2.1 in differentiating AEC. Inhibiting AEC differentiation in vitro with keratinocyte growth factor (KGF) maintained an AT2 cell phenotype through increased PI3K/AKT-mediated FOXO1 phosphorylation, resulting in higher levels of surfactant expression. Together these results indicate that FOXO1 plays a central role in AEC differentiation by directly binding NKX2.1 and suggests an essential role for FOXO1 in mediating AEC homeostasis.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据