Platelet-derived growth factor-stimulated expression of the MCP-1 immediate-early gene involves an inhibitory multiprotein complex

Mol Cell Biol. 1999 Jun;19(6):4219-30. doi: 10.1128/MCB.19.6.4219.

Abstract

We have demonstrated previously that the seven-nucleotide (nt) motif TTTTGTA (the heptamer) that is present within the proximal 3' untranslated sequences of numerous immediate-early genes is essential for platelet-derived growth factor (PDGF)-stimulated induction of the MCP-1 immediate-early gene. On this basis, the heptamer was suggested to be a conserved regulatory element involved in immediate-early gene expression, although its mechanism of action was unknown. Herein, we demonstrate that the heptamer functions to remove an inhibition of PDGF induction of MCP-1 maintained by two independently acting inhibitory elements present in the MCP-1 5' flanking sequences (designated I* elements). PDGF treatment relieves the I*-mediated inhibition of MCP-1 expression only if the heptamer is also present. One inhibitory element is contained within a 59-nt portion of MCP-1 5' flanking sequences and functions in an orientation-independent and heptamer-regulated manner. Significantly, proteins binding to two DNA sequences contribute to the formation of a single multiprotein complex on the 59-nt I* element. The I*-binding complex contains Sp3, an Sp1-like protein, and a novel DNA-binding protein. Moreover, the complex does not form on two 59-nt sequences containing mutations that reverse the inhibition of PDGF induction maintained by the wild-type I* element. We propose to call the multiprotein I*-binding complex a repressosome and suggest that it acts to repress PDGF-stimulated transcription of MCP-1 in the absence of the heptamer TTTTGTA.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • Blotting, Western
  • Chemokine CCL2 / antagonists & inhibitors
  • Chemokine CCL2 / genetics*
  • DNA Footprinting
  • DNA-Binding Proteins / metabolism
  • Deoxyribonuclease I / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Genes, Immediate-Early*
  • Mice
  • Models, Biological
  • Models, Genetic
  • Mutagenesis, Site-Directed
  • Plasmids
  • Platelet-Derived Growth Factor / physiology*
  • Precipitin Tests
  • Sp1 Transcription Factor / metabolism
  • Sp3 Transcription Factor
  • Transcription Factors / metabolism

Substances

  • Chemokine CCL2
  • DNA-Binding Proteins
  • Platelet-Derived Growth Factor
  • Sp1 Transcription Factor
  • Sp3 protein, mouse
  • Transcription Factors
  • Sp3 Transcription Factor
  • Deoxyribonuclease I