Cell- and ligand-specific regulation of promoters containing activator protein-1 and Sp1 sites by estrogen receptors alpha and beta.

ABSTRACT

Estrogen plays a critical role in development and maintenance of female reproductive and mammary tissues, but is also involved in maintenance of cardiovascular, skeletal, and neural function. Although it is widely accepted that the estrogen-occupied receptor mediates its effects by interacting with estrogen response elements (EREs) residing in target genes, a number of estrogen-responsive genes contain no identifiable ERE. To understand how estrogen-responsive genes lacking EREs but containing activator protein 1 (AP-1) and Sp1 sites respond to hormone treatment, we have identified four discrete regions of the human progesterone receptor gene that contain AP-1 or Sp1 sites and examined their abilities to modulate transcription in the presence of 17 beta-estradiol, ICI 182,780, tamoxifen, raloxifene, genistein, or daidzein. Transient cotransfection assays demonstrated that ER alpha was a more potent activator of transcription than ER beta in bone, uterine, and mammary cells. The Sp1-containing promoters were substantially more potent transcriptional enhancers than the AP-1-containing promoters, but a 1.5-kb region of the human progesterone receptor gene containing both AP-1 and Sp1 sites was the most hormone-responsive promoter tested. The ability of ligands to modulate transcription of AP-1- or Sp1-containing promoters was dependent on cell context, but the expression of AP-1 or Sp1 proteins was not necessarily related to transcriptional response. Taken together, these studies have helped to delineate the roles of ER alpha and ER beta in modulating transcription of genes containing AP-1 and Sp1 sites and define the effects of widely used, pharmacologic agents in target cells with distinct cellular environments.