A synthetic oestrogen antagonist, tamoxifen, inhibits oestrogen-induced transcriptional, but not post-transcriptional, regulation of gene expression

Abstract

Oestrogen (E2) regulates the expression of its target genes at transcriptional and post-transcriptional levels. To clarify the mechanism of E2-induced post-transcriptional regulation, with attention to the involvement of the oestrogen receptor (ER), we studied the effect of tamoxifen (TAM), a synthetic E2 antagonist that inhibits ER-mediated transcription, on E2-induced transcriptional and post-transcriptional regulation of the chicken ovalbumin (OVA) gene in chick oviducts. Run-on analysis with oviduct nuclei isolated from E2-treated chicks showed that TAM treatment completely blocked E2-induced transcription of the OVA gene within 24 h without affecting ER gene expression. Likewise, the rate of transcription fell to below the limit of detection after E2 withdrawal from the chicks. Reflecting the transcription rate, OVA mRNA accumulated linearly in E2-treated chicks, and E2 withdrawal caused a rapid loss of OVA mRNA. However, in the chicks treated with TAM and E2, OVA mRNA was degraded slowly over 48 h with a half-life of 24 h, suggesting that TAM does not inhibit E2-induced mRNA stabilization. Moreover, E2-induced mRNA stabilization was observed even when transcription of the OVA gene was blocked by a transcription inhibitor. Western-blot analysis showed that the remaining OVA mRNA was translatable. Thus the present study indicates that E2 regulates expression of the OVA gene via distinct pathways at transcriptional and post-transcriptional levels.