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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

Oncogene volume 26, pages 7872–7884 (2007)Cite this article

Abstract

Estradiol (E2) 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)-α P4 core promoter by ER is enhanced by E2 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 E2/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 E2/ER that was inhibited by Tam. In nuclear extracts, association of ER with a biotinylated core promoter fragment was promoted by E2 but Tam blocked this effect. Repression/de-repression of the P4 promoter and endogenous FR-α expression by E2/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 E2 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.

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Acknowledgements

Several plasmid constructs were kind gifts received from Drs Stephen Safe, Zafar Nawaz and Brian Rowan. T47D-B cells were a kind gift from Dr Katherine Horwitz. Lentivirus pLL3.7 and plasmids pMD2G, pMDLg/pRRE and pRSV-Rev were kindly provided by Dr Kam Yeung. We thank Mariana Stoeva for technical support. This work was supported by NIH grants CA 80183 and CA 103964 to MR.

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  1. H Hao and M d'Alincourt-Salazar: These two authors contributed equallyto this work.

Authors and Affiliations

  1. Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, OH, USA

    H Hao, M d'Alincourt-Salazar, K M M Kelley, A Shatnawi, S Mukherjee, Y M Shah & M Ratnam

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  1. H Hao
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  2. M d'Alincourt-Salazar
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Correspondence to M Ratnam.

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Hao, H., d'Alincourt-Salazar, M., Kelley, K. et al. 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. Oncogene 26, 7872–7884 (2007). https://doi.org/10.1038/sj.onc.1210592

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