Platelet-derived growth factor stimulation of monocyte chemoattractant protein-1 gene expression is mediated by transient activation of the phosphoinositide 3-kinase signal transduction pathway

J Biol Chem. 1999 Oct 22;274(43):31062-7. doi: 10.1074/jbc.274.43.31062.


Platelet-derived growth factor (PDGF) stimulates transcription of an immediate-early gene set in Balb/c 3T3 cells. One cohort of these genes, typified by c-fos, is induced within minutes following activation of PDGF receptors. A second cohort responds to PDGF only after a significant time delay, although induction is still a primary response to receptor activation as shown by "superinduction" in the presence of the protein synthesis inhibitor cycloheximide. PDGF-receptor activated signaling pathways for the "slow" immediate-early genes are poorly resolved. Using gain-of-function mutations together with small molecule inhibitors of kinase activity, we show that activation of PI 3-kinase is both necessary and sufficient for the induction of the prototype slow immediate-early gene, monocyte chemoattractant-1 (MCP-1). Following activation of PDGF receptors, MCP-1 mRNA does not begin to accumulate for at least 90 min. However, only a brief (10 min) interval of PI 3-kinase activity is required to trigger this delayed response. The serine/threonine protein kinase, Akt/PKB, likely functions as a downstream affector of PI 3-kinase for this induction.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Androstadienes / pharmacology
  • Animals
  • Becaplermin
  • Chemokine CCL2 / genetics*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Genes, fos
  • Interleukin-1 / pharmacology
  • Kinetics
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Platelet-Derived Growth Factor / pharmacology*
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger / genetics
  • Receptors, Platelet-Derived Growth Factor / physiology*
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transcription, Genetic / drug effects
  • Transfection
  • Wortmannin


  • Androstadienes
  • Chemokine CCL2
  • Enzyme Inhibitors
  • Interleukin-1
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger
  • Recombinant Proteins
  • Becaplermin
  • Phosphatidylinositol 3-Kinases
  • Receptors, Platelet-Derived Growth Factor
  • Mitogen-Activated Protein Kinases
  • Wortmannin