Diversity in the mechanisms of gene regulation by estrogen receptors

Abstract

The sequencing of the human genome has opened the way for using bioinformatics to identify sets of genes controlled by specific regulatory signals. Here, we review the unexpected diversity of DNA response elements mediating transcriptional regulation by estrogen receptors (ERs), which control the broad physiological effects of estrogens. Consensus palindromic estrogen response elements are found in only a few known estrogen target genes, whereas most responsive genes contain only low-affinity half palindromes, which may also control regulation by other nuclear receptors. ERs can also regulate gene expression in the absence of direct interaction with DNA, via protein-protein interactions with other transcription factors or by modulating the activity of upstream signaling components, thereby significantly expanding the repertoire of estrogen-responsive genes. These diverse mechanisms of action must be taken into account in screening for potential estrogen-responsive sequences in the genome or in regulatory regions of target genes identified by expression profiling.

Induction of Hsp22 (HspB8) by estrogen and the metalloestrogen cadmium in estrogen receptor– positive breast cancer cells

“…Usually, such imperfect elements on their own have only weak transcriptional activity, whereas 2 or more imperfect elements throughout the regulatory sequences of E 2 -responsive genes can cooperate for ER binding and transactivation (Kato et al 1992). In addition, individual ERE 1/2 sites can be associated with binding sites for the transcription factor Sp1 (GC boxes or GT/CACC boxes), and the significance of these associated ER/Sp1-binding sites for the response to E 2 was demonstrated (Sanchez et al 2002).…”

“…The effect of E 2 is mediated through its ability to bind to the ␣ and ␤ forms of the estrogen receptor (ER), a ligandactivated transcription factor. The estrogenic response is complex, both in terms of the number of responsive genes, the involved regulatory mechanisms and molecules, and even the consequences for tumor growth (Rochefort 1995;Ohlsson et al 2001;Sanchez et al 2002). Various anti-estrogens have been widely used for both research and treatment of ER-positive (ER ϩ ) breast cancer in patients.…”

Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

“…Examples are insulin-like growth factor, epidermal growth factor, and transforming growth factor-beta, which act by binding to receptors on the cell membrane, and c-Fos and c-Jun, transcription factors that bind to AP-1 sites [9][10][11]25]. Cross-talk between these proteins and the five steroid receptors increases the combinatorial complexity for regulation of development in vertebrates.…”

“…1) [5][6][7][8], which is a ligand-based based mechanism for regulating the interactions between networks of transcription factors [9][10][11], as well as directly regulating the transcription of specific genes. Receptors for these steroids have not been found in invertebrates.…”

Estrogen receptors: Their roles in regulation of vasopressin release for maintenance of fluid and electrolyte homeostasis

“…Unlike some steroid receptors (e.g. glucocorticoid receptors), the nuclear localization of ERs is not dependent on a steroid ligand binding to the receptor, and evidence exists for ligand-independent, gene regulatory effects of ERs [50,60]. The rectangles in B and D indicate regions shown at higher magnification in C and E respectively.…”