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Role of CBP/p300 and SRC-1 in transcriptional regulation of the pulmonary surfactant protein-A (SP-A) gene by thyroid transcription factor-1 (TTF-1).

Surfactant protein-A (SP-A) gene expression is developmentally regulated in fetal lung type II cells and is enhanced by cAMP. cAMP stimulation of SP-A gene expression is mediated by protein kinase A (PKA) phosphorylation of thyroid transcription factor 1 (TTF-1), expressed selectively in developing lung epithelium. In this study, we analyzed roles of CREB-binding protein (CBP) and steroid receptor coactivator-1 (SRC-1) in TTF-1 regulation of SP-A expression. Upon differentiation of human fetal lung in culture, nuclear localization of CBP, SRC-1, and TTF-1 increased in ductular epithelium in association with type II cell differentiation and induction of SP-A expression. In transient transfections, CBP and SRC-1 acted synergistically with TTF-1 to increase SP-A promoter activity. Overexpression of PKA catalytic subunit enhanced hSP-A promoter activation by SRC-1 plus TTF-1. Adenoviral E1A overexpression reduced TTF-1 +/- SRC-1 induction of SP-A promoter activity, suggesting a role of endogenous CBP/p300. TTF-1 interacted with SRC-1 and CBP in vitro. SRC-1 immunodepletion from type II cell nuclear extracts reduced binding to the TTF-1 binding element upstream of SP-A gene. In cultured type II cells, cAMP increased TTF-1 acetylation. This suggests that cAMP-mediated TTF-1 phosphorylation facilitates interaction with CBP and SRC-1, resulting in its hyperacetylation, further enhancing TTF-1 DNA-binding and transcriptional activity.

Pubmed ID: 11713256

Authors

  • Yi M
  • Tong GX
  • Murry B
  • Mendelson CR

Journal

The Journal of biological chemistry

Publication Data

January 25, 2002

Associated Grants

  • Agency: NHLBI NIH HHS, Id: R37HL50022

Mesh Terms

  • Adenoviridae
  • CREB-Binding Protein
  • Catalytic Domain
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinase Type II
  • Cyclic AMP-Dependent Protein Kinases
  • DNA
  • Electrophoresis, Polyacrylamide Gel
  • Glutathione Transferase
  • Histone Acetyltransferases
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Lung
  • Models, Biological
  • Nuclear Proteins
  • Nuclear Receptor Coactivator 1
  • Phosphorylation
  • Plasmids
  • Promoter Regions, Genetic
  • Protein Binding
  • Proteolipids
  • Pulmonary Alveoli
  • Pulmonary Surfactant-Associated Protein A
  • Pulmonary Surfactant-Associated Proteins
  • Pulmonary Surfactants
  • Time Factors
  • Trans-Activators
  • Transcription Factors
  • Transcription, Genetic
  • Transfection