Estrogen-induced and TAFII30-mediated gene repression by direct recruitment of the estrogen receptor and co-repressors to the core promoter and its reversal by tamoxifen

Abstract

Estradiol (E 2 ) acts through the estrogen receptor (ER) to downregulate many genes, and tamoxifen (Tam) largely reverses this repression but the underlying mechanisms are unclear. Repression of the folate receptor (FR)-a P4 core promoter by ER is enhanced by E 2 and reversed by Tam. This effect was unaffected by inhibition of new protein synthesis and required the E/F and the DNA-binding domains of ER without direct binding of ER to DNA. The repression by E 2 /ER was not specific for either Sp1 or TATA elements but was loosely selective for the initiator and flanking sequence. Insertion of a response element or a relatively strong Sp1 cluster to recruit ER upstream of the core promoters caused a switch to activation by E 2 /ER that was inhibited by Tam. In nuclear extracts, association of ER with a biotinylated core promoter fragment was promoted by E 2 but Tam blocked this effect. Repression/ de-repression of the P4 promoter and endogenous FR-a expression by E 2 /Tam required SMRT and/or NCoR. ER associated with the chromosomal P4 promoter and SMRT and NCoR associated with it in an ER-dependent manner; these associations were favored by E 2 but disrupted by Tam, in the short term, without changes in ER expression. TAFII30 was required for optimal P4 promoter activity and for the repressive association of ER. E2 may thus maintain a low transcriptional status of genes by favoring direct TAFII30-dependent association of ER with the core promoter in a co-repressor complex containing SMRT and/or NCoR; this repression is overridden in target genes containing an upstream element that strongly recruits ER. In addition to suppressing the activation of classical E2 target genes, Tam may upregulate genes by passively dissociating the ER co-repressor complex.

Repression of ESR1 through Actions of Estrogen Receptor Alpha and Sin3A at the Proximal Promoter

“…This was a surprising finding given the importance of distal sites in models of E2 activation (9,44,61). However, review of the limited reports on E2 repression of genes shows that the elements necessary for repression reside at or near the transcription start site (2,22,25,43,59,60,64,71). We noted greater variability in ER␣ occupancy at ESR1 compared to activated pS2.…”

“…Microarray analyses of E2-treated breast cancer cell lines show that the number of repressed genes is greater than or near the number of activated genes (10,19,29,32). Yet, there are limited reports investigating E2-induced repression, and no generalized mechanism has emerged (6,13,22,25,43,47,59,60,71,74). Antagonistinduced repression by selective ER modulators involves conformational changes that prevent coactivator binding to ER␣ (55).…”

Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element

“…2C), suggesting that the suppressive effect of E2 on FPN was through a transcriptional mechanism, rather than a translational mechanism. Additionally, tamoxifen, which acts as an antagonist of E2 action by binding to ER, [35] notably reversed this inhibitory effect at the concentration of 1 μM (Fig. 2D), further indicating that FPN could be modulated through E2 signaling pathway.…”

Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1

“…In our laboratory and elsewhere, a direct role of ER␣ and of corepressor/histone deacetylase (HDAC)-containing complexes has been demonstrated in the regulation of some estrogen (E2)-repressed target genes (32,40). Carroll et al (5) have highlighted a role for the coregulator NRIP1/RIP140 in the regulation of late E2-repressed target genes, while other mechanisms proposed to be involved in ER␣-mediated transcriptional repression include physiological squelching of coactivator proteins and involvement of components of the basal transcriptional machinery (7,19).…”