Transcriptional Activation of the Oxytocin Promoter by Oestrogens Uses a Novel Non-classical Mechanism of Oestrogen Receptor Action

Transcriptional activation of the gene coding for the neuropeptide hormone oxytocin by oestrogens does not follow the classical model of oestrogen receptor action. The oxytocin promoter does not contain an oestrogen response element (ERE), but instead a high-affinity binding site for nuclear orphan receptors. In the present study, the oestrogen-dependent up-regulation of the bovine oxytocin promoter is investigated in MDA-MB 231 cells. Control by oestrogen is shown to be dependent on the integrity of the nuclear orphan receptor binding site and the presence of ligand-activated oestrogen receptor, but independent of oestrogen receptor binding to DNA. Partial agonists tamoxifen and raloxifen and the pure antagonist ICI 182 780 all show agonistic activities on transcription, while exhibiting normal binding affinities to oestrogen receptor (ER)alpha. Nuclear orphan receptors oestrogen receptor-related receptor alpha (ERRalpha) and germ cell nuclear factor (GCNF) are expressed to significant levels in MDA-MB 231 cells. Binding of ERRalpha to the oxytocin promoter binding site can be demonstrated, suggesting the involvement of this nuclear orphan receptor in oestrogen-dependent up-regulation. The oestrogenic stimulation of the oxytocin promoter apparently is dependent on the stimulation of the transcriptional activity of this nuclear orphan receptor by ERK-1/ERK-2 mitogen-activated protein kinases (MAP kinases). This novel nonclassical mechanism of oestrogen action most probably is not restricted to the regulation of neuropeptide hormone expression, but may further contribute to the multitude of tissue-specific effects of oestrogenic substances.