Fos and Jun inhibit estrogen-induced transcription of the human progesterone receptor gene through an activator protein-1 site

Mol Endocrinol. 2004 Mar;18(3):521-32. doi: 10.1210/me.2003-0105. Epub 2003 Dec 18.


The progesterone receptor (PR) gene is activated by estrogen in normal reproductive tissues and in MCF-7 human breast cancer cells. Although it is typically thought that estrogen responsiveness is mediated through estrogen response elements (EREs), the human PR gene lacks a palindromic ERE sequence. We have identified an activating protein-1 (AP-1) site at +745 in the human PR gene that bound purified Fos and Jun and formed a complex with Fos/Jun heterodimers present in MCF-7 nuclear extracts. Surprisingly, mutating the +745 AP-1 site in the context of a 1.5-kb region of the PR gene significantly enhanced estrogen receptor (ER) alpha-mediated transactivation, suggesting that the wild-type +745 AP-1 site plays a role in inhibiting PR gene expression in the presence of hormone. In support of this idea, transient transfection assays demonstrated that increasing levels of Fos and Jun repressed transcription of a reporter plasmid containing the +745 AP-1 site. Fos levels were transiently increased, ERalpha levels were decreased, and Jun was dephosphorylated after MCF-7 cells were treated with estrogen. Chromatin immunoprecipitation assays demonstrated that Jun was associated with the +745 AP-1 site in the endogenous PR gene in the presence and in the absence of estrogen, but that ERalpha and Fos were only associated with the +745 AP-1 site after estrogen treatment of MCF-7 cells. Our studies suggest that the human PR gene is regulated by multiple transcription factors and that the differential binding of these dynamically regulated trans-acting factors influences gene expression.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Cells, Cultured
  • Chromatin / genetics
  • Chromatin / metabolism
  • Conserved Sequence
  • Estradiol / pharmacology
  • Estrogen Receptor alpha
  • Estrogens / pharmacology
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mutation
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / isolation & purification
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / isolation & purification
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Rabbits
  • Rats
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / drug effects
  • Receptors, Progesterone / genetics*
  • Receptors, Progesterone / metabolism
  • Response Elements
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic


  • Chromatin
  • Estrogen Receptor alpha
  • Estrogens
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Transcription Factor AP-1
  • Estradiol