ERa transcriptional activation

ERa Transcriptional Activation AR Binding1 Steroidogenesis H295R Aromatase Recombinant In vivo Uterotrophic Hershberger Pubertal Male Pubertal Female Amphibian Metamorphosis Fish Short-term Reproduction (male female)... 

Of these active metabolites, endoxifen is suggested to be the primary active metabolite responsible for the majority of tamoxifen clinical efficacy, as endoxifen plasma concentrations are about five to tenfold higher than those of 4-hydroxy-tamoxifen [11, 165], Endoxifen may have additional mechanisms of action than 4-hydroxy-tamoxifen by targeting Era for degradation by proteasome [166] and through the promotion of ERa/ERf) heterodimerization, blocking ERa transcriptional activity [167],... 

ERa serves as an example of a TF that is dependent on an HDAC for its activity (84). The reduction in expression of this nuclear receptor is a key step in the carcinogenesis of breast cancer and correlates with poor prognosis. ERa has been shown to bind HDACl directly in vitro and in vivo, and the overexpression of HDACl in MCF-7 cells leads to a reduction in both ERa protein levels and ERa transcriptional activity. Overexpression of HDACl also causes increased cell proliferation of MCE-7 cells (96). Thus, it has been suggested that HDACl plays a critical role in breast cancer progression. Consistent with this... 

Hall, J.M. and McDonnell, D.P. (1999) The estrogen receptor p-isoform (ERp) of the human estrogen receptor modulates ERa transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology, 140, 5566-5578. 

Mclnerney EM, Weis KE, Sun J, Mosselman S, Katzenellenbogen BS (1998) Transcription activation by the human estrogen receptor subtype beta (ERb) studied with ERa and ERb receptor chimeras. Endocrinology 139 4513... 

Recently, a Japanese research group published preclinical safety and efficacy data of an oral antiestrogen (TZE-5323) (Saito et al. 2003). This drug has been shown to have a strong affinity for human ERa and ER/i and a dose-dependent capacity to inhibit estradiol-stimulated transcriptional activation (Saito et al. 2003). In the experimental endometriosis model in rats, TZE-5323 dose-dependently reduced the volume of the endometrial implant with an effectiveness similar to that of danazol and leuprorelin acetate without causing significant changes in bone mineral density and in serum estradiol levels (Saito et al. 2003). 

The potential impact of the chromatin structure on ERa- and ER/1-mediated transcriptional activities was investigated using an in vitro chromatin assembly assay. These experiments have shown that the AF-1 domain of ERa, but not of ER/1, contains a transferable activation domain, which permits the ERa to efficiently activate transcription on chromatin templates [58]. Furthermore, the co-activators CBP/p300 and SRC have to be recruited to the ERa in order to maximally enhance transcription on ERa-susceptible chromatin templates. The p300/CBP-SRC complex, when interacting with the AF-1 of the ERa, is primarily involved in the stable formation of the preinitiation complex of transcription [59]. 

Furthermore, post-translational modifications activate steroid hormone receptors in a ligand-independent fashion (Fig. 5), as shown for the ERa which is phosphorylated on serine residue 118 in the AF-1 domain by the Erkl/2 kinase [71]. In vitro, the serine-118 phosphorylated ERa is transcriptionally active in a ligand-independent fashion. 

The coactivator SRC-1 has been shown to interact with and promote the transcriptional activity of a number of nuclear receptors, including ERa (Mclnemey et al., 1996 Onate et al., 1995). More recently, we have demonstrated that SRC-1 also stimulates ERp activity through a direct interaction with its LBD, where the AF-2 domain resides (Tremblay et... 

Fig. 16. Basal ERp transcriptional activation by SRC-1 is AF-2 independent. (A) Dose-dependent activation of ERa and ERP by SRC-1 in absence of Eg. Cos-1 cells were transfected with ERETKLuc reporter along with ERa or ERP and increasing amounts of SRC-1 expression plasmids. Luciferase activities were normalized with P-Gal expression and results are expressed as factor by which response exceeds basal levels (-) and represent the mean SEM of three independent experiments. (B) Pure antiestrogen EM-652 but not the mixed antagonist 4-hydroxytamoxifen (OHT) inhibits basal ERP transcriptional activation by SRC-1. Cos-1 cells were transfected with ERETKLuc along with equivalent amounts of ERP and SRC-1 expression plasmids and incubated with increasing amounts of OHT or EM-652 prior to being assayed for luciferase activity. The maximal induction by SRC-1 alone (solid bar) was defined as 100%. Basal level in absence of SRC-1 is indicated by an open bar. (C) Basal activity of an ERP AF-2 mutant is induced by SRC-1. Cos-1 cells were transfected with ERETKLuc reporter and equivalent amounts of ERP or ERP L509A AF-2 mutant and SRC-1 (solid bars) expression plasmids. Cells were then treated with 10 nM Eg (striated bars) or left untreated (open and solid bars) for 16 hours prior to harvest. Results are plotted as factor by which induction exceeds basal levels (Tremblay et al, 1999).

The low homology between ERa and ER(3 in the N-terminal A/B domain indicates different patterns of gene activation between these two receptors. Construction of ER(3 chimeras with ERa A/B domain exhibited an improved transcriptional response to estrogens and antiestrogens and indicated that differences in the N-terminal and contribute to cell- and promotor-specific differences in transcriptional activity of ERa and ER(3 (M14). 

The oestrogen receptor (ERa)has, like all SHRs, a modular structure with two transcriptional activation functions, AF-1 and AF-2. AF-1 is in the NH2-terminal and AF-2 in the carboxy-termmal region. Besides ERa. there exists another ER, ERp. The existence of ERp explains why tissues, such as the ovaries and the urogenital tract, which have no ERa, are still responsive to oestrogen, (see ref. 19). More than one ER also explains why mice without one of the oestrogen receptors have no oestrogen-related... 

Tetrahydroquinolines and Tetrahydroisoquinolines Various tetrahydroquinoline and tetrahydroisoquinoline variants of lasofoxifene have been investigated. Novartis reported ERa-selective tetrahydroisoquinolines. The archetype structure showed good affinity and 16-fold selectivity for ERa. Introduction of a methyl group at Cl slightly lowered ERa selectivity, but increased transcriptional activity in HeLa cells... 

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