A proximal activator of transcription in epithelial-mesenchymal transition

J Clin Invest. 2007 Feb;117(2):482-91. doi: 10.1172/JCI29544.

Abstract

Epithelial-mesenchymal transition (EMT) is an important mechanism for phenotypic conversion in normal development and disease states such as tissue fibrosis and metastasis. While this conversion of epithelia is under tight transcriptional control, few of the key transcriptional proteins are known. Fibroblasts produced by EMT express a gene encoding fibroblast-specific protein 1 (FSP1), which is regulated by a proximal cis-acting promoter element called fibroblast transcription site-1 (FTS-1). In mass spectrometry, chromatin immunoprecipitation, and siRNA studies, we used FTS-1 as a unique probe for mediators of EMT and identified a complex of 2 proteins, CArG box-binding factor-A (CBF-A) and KRAB-associated protein 1 (KAP-1), that bind this site. Epithelial cells engineered to conditionally express recombinant CBF-A (rCBF-A) activate the transcription of FSP1 and undergo EMT. The FTS-1 response element also exists in the promoters modulating a broader EMT transcriptome, including Twist, and Snail, as well as E-cadherin, beta-catenin, ZO 1, vimentin, alpha1(I) collagen, and alpha-smooth muscle actin, and the induction of rCBF-A appropriately alters their expression as well. We believe formation of the CBF-A/KAP-1/FTS-1 complex is sufficient for the induction of FSP1 and a novel proximal activator of EMT.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CCAAT-Binding Factor / genetics
  • CCAAT-Binding Factor / metabolism
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • DNA Primers / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epithelium / metabolism*
  • Male
  • Mesoderm / cytology
  • Mesoderm / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological
  • Molecular Sequence Data
  • Multiprotein Complexes
  • NIH 3T3 Cells
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Tripartite Motif-Containing Protein 28

Substances

  • CCAAT-Binding Factor
  • Calcium-Binding Proteins
  • DNA Primers
  • DNA-Binding Proteins
  • Multiprotein Complexes
  • Nfyb protein, mouse
  • Nuclear Proteins
  • Repressor Proteins
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • Transcription Factors
  • Trim28 protein, mouse
  • Tripartite Motif-Containing Protein 28