GHF-1/Pit-1 functions as a cell-specific integrator of Ras signaling by targeting the Ras pathway to a composite Ets-1/GHF-1 response element

J Biol Chem. 1996 Oct 4;271(40):24639-48. doi: 10.1074/jbc.271.40.24639.


Activation of the rat prolactin (rPRL) promoter by Ras is a prototypical example of tissue-specific transcriptional regulation in a highly differentiated cell type. Using a series of site-specific mutations and deletions of the proximal rPRL promoter we have mapped the major Ras/Raf response element (RRE) to a composite Ets-1/GHF-1 binding site located between positions -217 and -190. Mutation of either the Ets-1 or GHF-1 binding sites inhibits Ras and Raf activation of the rPRL promoter, and insertion of this RRE into the rat growth hormone promoter confers Ras responsiveness. We show that Ets-1 is expressed in GH4 cells and, consistent with their functional synergistic interaction, both Ets-1 and GHF-1 are able to bind specifically to this bipartite RRE. We confirm that Ets-1 or a related Ets factor is the nuclear target of the Ras pathway leading to activation of the rPRL promoter and demonstrate that Elk-1 and Net do not mediate the Ras response. Thus, the pituitary-specific POU homeodomain transcription factor, GHF-1, serves as a cell-specific signal integrator by functionally interacting with an Ets-1-like factor, at uniquely juxtaposed binding sites, thereby targeting an otherwise ubiquitous Ras signaling pathway to a select subset of cell-specific GHF-1-dependent genes.

Publication types

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

MeSH terms

  • Animals
  • DNA-Binding Proteins / metabolism*
  • Homeodomain Proteins / metabolism*
  • Mutagenesis, Site-Directed
  • Oncogene Proteins*
  • Pituitary Gland / cytology
  • Pituitary Gland / metabolism
  • Prolactin / genetics
  • Promoter Regions, Genetic
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-ets
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Rats
  • Signal Transduction*
  • Transcription Factor Pit-1
  • Transcription Factors / metabolism*
  • Transduction, Genetic
  • Tumor Cells, Cultured
  • ets-Domain Protein Elk-1


  • DNA-Binding Proteins
  • Elk1 protein, rat
  • Elk3 protein, mouse
  • Ets1 protein, mouse
  • Ets1 protein, rat
  • Homeodomain Proteins
  • Oncogene Proteins
  • Pou1f1 protein, rat
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Transcription Factor Pit-1
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Prolactin
  • Proto-Oncogene Proteins p21(ras)