Ligand-Independent Activation of the Estrogen Receptor: Activation by Epidermal Growth Factor and Dopamine

Abstract

The estrogen receptor (ER) is a member of a large family of transcription factors including steroid/thyroid hormone receptors (Evans 1988). These receptors share a conserved structural and functional organization, which includes separable domains for hormone binding (HBD), DNA binding, and transcriptional activation (Tsai and O’Malley 1994). Like other members of the nuclear hormone receptor superfamily, ER has at least two transcriptional activation functions (AFs), one in its amino-terminal region (AF-1) and the second in its carboxy-terminal, ligand-binding region (AF-2) (Kumar et al. 1987; Webster et al. 1988). According to the classical model of steroid hormone action, hormone enters cells by passive diffusion where it binds to and induces a conformational change in its cognate receptor protein. This leads to the release of the inhibitory heat shock protein 90 complex, nuclear translocation, interaction with chromatin, and modulation of gene expression. Steroid receptors can activate transcription of genes containing in their 5’ flanking region a specific DNA sequence called the hormone response element (HRE; ERE for ER). Before and upon ligand binding, ER is phosphorylated at several sites (Ali et al. 1993; Le Goff et al. 1994). The importance of phosphorylation in modulating transcriptional functions of ER, as well as of other steroid receptors, has been highlighted by correlative studies suggesting that phosphorylation may be involved in modulating either steroid binding, DNA binding or transactivation (Bagchi et al. 1992; Takimoto et al. 1992).