Nuclear factor I/thyroid transcription factor 1 interactions modulate surfactant protein C transcription

Mol Cell Biol. 2003 Dec;23(24):9014-24. doi: 10.1128/MCB.23.24.9014-9024.2003.

Abstract

Surfactant protein C (SP-C; Sftpc) gene expression is restricted to pulmonary type II epithelial cells. The proximal SP-C promoter region contains critical binding sites for nuclear factor I (NFI) and thyroid transcription factor 1 (TTF-1; also called Nkx2.1). To test the hypothesis that NFI isoforms interact with TTF-1 to differentially regulate SP-C transcription, we performed transient transfection assays in JEG-3 cells, a choriocarcinoma cell line with negligible endogenous NFI or TTF-1 activity. Cotransfection of NFI family members with TTF-1 induced synergistic activation of the SP-C promoter that was further enhanced by p300. TTF-1 directly interacts with the conserved DNA binding and dimerization domain of all NFI family members in coimmunoprecipitation and mammalian two-hybrid experiments. To determine whether SP-C expression is regulated by NFI in vivo, a chimeric fusion protein containing the DNA binding and dimerization domain of NFI-A and the Drosophila engrailed transcriptional repression domain (NFIen) was conditionally expressed in mice under control of a doxycycline-inducible transgene. Induction of NFIen in a subset of type II cells inhibited SP-C gene expression without affecting expression of TTF-1 in doxycycline-treated double-transgenic mice. Taken together, these findings support the hypothesis that NFI family members interact with TTF-1 to regulate type II cell function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cell Line, Tumor
  • DNA / genetics
  • DNA-Binding Proteins*
  • Humans
  • Mice
  • Mice, Transgenic
  • NFI Transcription Factors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic
  • Protein Isoforms / metabolism
  • Pulmonary Surfactant-Associated Protein C / genetics*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Thyroid Nuclear Factor 1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Y-Box-Binding Protein 1

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • NFI Transcription Factors
  • NFIA protein, human
  • NKX2-1 protein, human
  • Nfia protein, mouse
  • Nkx2-1 protein, mouse
  • Nuclear Proteins
  • Protein Isoforms
  • Pulmonary Surfactant-Associated Protein C
  • Recombinant Fusion Proteins
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • Y-Box-Binding Protein 1
  • YBX1 protein, human
  • DNA