title: Inhibition of β-catenin/p300 interaction proximalizes mouse embryonic lung epithelium.
abstract: BACKGROUND
  Wnt/β-catenin signaling has been suggested to regulate proximal-distal determination of embryonic lung epithelium based upon genetically modified mouse models. The previously identified and characterized small molecule inhibitor IQ1 can pharmacologically decrease the interaction between β-catenin and its transcriptional coactivator p300, thereby enhancing the β-catenin/CBP interaction. Inhibition of the β-catenin/p300 interaction by IQ1 blocks the differentiation of embryonic stem cells and epicardial progenitor cells; however, whether differential coactivator usage by β-catenin plays a role in proximal-distal determination of lung epithelium is unknown.
  
  
  METHODS
  We examined the effects of inhibiting the β-catenin/p300 interaction with IQ1 on lung branching morphogenesis in mouse embryos in utero and mouse embryonic lung organ culture ex vivo. The phenotype of IQ1 treated lungs was analyzed by epithelial staining, histology, quantitative PCR and in situ hybridization.
  
  
  RESULTS
  Inhibition of the β-catenin/p300 interaction by IQ1 disrupted the distal branching of mouse lung epithelium both in utero and ex vivo. IQ1 proximalized lung epithelium with decreased expression of the genes Bmp4 and Fgf10, hallmarks of distal lung determination, and increased expression of the proximal genes Sox2 and Scgb1a1 (CC10) as shown by quantitative PCR and in situ hybridization. The disruption of branching was reversible ex vivo as branching was reinitiated after removal of IQ1 from the media.
  
  
  CONCLUSIONS
  The results demonstrate that the β-catenin/p300 interaction plays a critical role in proximal-distal determination of the epithelium in mouse lung branching morphogenesis and β-catenin/p300 inhibition pharmacologically proximalizes lung epithelium.
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Los Angeles, CA 90033 USA.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Los Angeles, CA 90033 USA ; Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Los Angeles, CA 90033 USA ; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Los Angeles, CA 90033 USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
keywords: Branching; CBP; Differentiation; ICG-001; IQ1; Lung; Small molecule inhibitor; Wnt; p300; β-catenin