Activation of the c-fos enhancer by the erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

Oncogene. 2000 Mar 9;19(11):1379-85. doi: 10.1038/sj.onc.1203443.


The c-fos enhancer can be activated by many signaling pathways through distinct elements of the enhancer. The enhancer contains at its core the serum response element (SRE) that binds serum response factor (SRF). On the 5' side of the SRE is a site for p62TCF which binds only when SRF is bound as well. p62TCF is encoded by three ets-related genes, Elk-1, SAP1 and SAP2. Each of these factors contain a transcriptional activation domain that is activated by phosphorylation by MAP kinases. On the 3' side of the SRE is the 'c-fos AP1 site' (FAP1) whose role has been less clear. We find here that the FAP1 site contributes strongly to phorbol ester (TPA) and Erk MAP kinase activation of the c-fos enhancer and that both the p62TCF and FAP1 sites are required for effective activation of the enhancer. We further find that the FAP1 site binds ATF1 and CREB from HeLa nuclear extracts and that the phosphorylation of these factors is induced by TPA. ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.

Publication types

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

MeSH terms

  • Activating Transcription Factor 1
  • Binding Sites / genetics
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / immunology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP Response Element-Binding Protein / physiology
  • DNA-Binding Proteins / physiology*
  • Enhancer Elements, Genetic* / drug effects
  • Enzyme Activation / drug effects
  • Gene Expression Regulation* / drug effects
  • Genes, fos* / drug effects
  • HeLa Cells
  • Heymann Nephritis Antigenic Complex
  • Humans
  • Immune Sera / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics*
  • Membrane Glycoproteins / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • Ribosomal Protein S6 Kinases / physiology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Activating Transcription Factor 1
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Heymann Nephritis Antigenic Complex
  • Immune Sera
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-fos
  • Transcription Factor AP-1
  • Transcription Factors
  • p62TCF protein, human
  • Proto-Oncogene Proteins c-raf
  • Ribosomal Protein S6 Kinases
  • Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate