Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element

Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11217-22. doi: 10.1073/pnas.96.20.11217.

Abstract

Estrogens induce cell proliferation in target tissues by stimulating progression through the G(1) phase of the cell cycle. Induction of cyclin D1 expression is a critical feature of the mitogenic action of estrogen. We have determined a region between -96 and -29 in the cyclin D1 promoter that confers regulation by estrogens in the human mammary carcinoma cells MCF-7. This region encompasses a unique known transcription factor binding site with a sequence of a potential cAMP response element (CRE-D1). The induction is strictly hormone dependent and requires the DNA binding domain as well as both AF-1 and AF-2 domains of the estrogen receptor (ER) alpha. Destruction of the CRE-D1 motif caused complete loss of estrogen responsiveness. Both c-Jun and ATF-2 transactivated the cyclin D1 promoter in transient transfection experiments, and a clear additional increase was detected when ER was cotransfected with either c-Jun or with c-Jun and ATF-2 but not with ATF-2 alone. Furthermore, the expression of a dominant negative variant of c-Jun, TAM67, completely abolished the induction of the cyclin D1 promoter both in the absence and presence of ER. We show that ATF-2 homodimers and ATF-2/c-Jun heterodimers, but not c-Jun homodimers, were able to bind the CRE of the cyclin D1 promoter. To interpret these results, we propose a mechanism in which ATF-2/c-Jun heterodimers bind to the CRE-D1 element and mediate the activation of cyclin D1 promoter by the ER. This mechanism represents a pathway by which estrogens control the proliferation of target cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2
  • Cyclic AMP / pharmacology*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclin D1 / genetics*
  • Estrogens / pharmacology*
  • HeLa Cells
  • Humans
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Receptors, Estrogen / metabolism
  • Response Elements*
  • Transcription Factors / metabolism

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • Estrogens
  • Proto-Oncogene Proteins c-jun
  • Receptors, Estrogen
  • Transcription Factors
  • Cyclin D1
  • Cyclic AMP