Ligand-independent activation of the oestrogen receptor by mutation of a conserved tyrosine

Open Access
Publisher Website
Google Scholar
Abstract
The oestrogen receptor is a member of the nuclear receptor family of transcription factors which, on binding the steroid hormone 17β‐oestradiol, interacts with co‐activator proteins and stimulates gene expression. Replacement of a single tyrosine in the hormone‐binding domain generated activated forms of the receptor which stimulated transcription in the absence of hormone. This increased activation is related to a decrease in hydrophobicity and a reduction in size of the side chain of the amino acid with which the tyrosine is replaced. Ligand‐independent, in common with ligand‐dependent transcriptional activation, requires an amphipathic α‐helix at the C‐terminus of the ligand‐binding domain which is essential for the interaction of the receptor with a number of potential co‐activator proteins. In contrast to the wild‐type protein, constitutively active receptors were able to bind both the receptor‐interacting protein RIP‐140 and the steroid receptor co‐activator SRC‐1 in a ligandindependent manner, although in the case of SRC‐1 this was only evident when the receptors were pre‐bound to DNA. We propose, therefore, that this tyrosine is required to maintain the receptor in a transcriptionally inactive state in the absence of hormone. Modification of this residue may generate a conformational change in the ligand‐binding domain of the receptor to form an interacting surface which allows the recruitment of co‐activators independent of hormone binding. This suggests that this tyrosine may be a target for a different signalling pathway which forms an alternative mechanism of activating oestrogen receptor‐mediated transcription.