The Relative Contribution Exerted by AF-1 and AF-2 Transactivation Functions in Estrogen Receptor α Transcriptional Activity Depends upon the Differentiation Stage of the Cell

Mérot, Yohann; Métivier, Raphaël; Penot, Graziella; Manu, Dominique; Saligaut, Christian; Gannon, Frank; Pakdel, Farzad; Kah, Olivier; Flouriot, Gilles

doi:10.1074/jbc.m402148200

Cited by 73 publications

(98 citation statements)

References 51 publications

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“…3A). A dose-response curve established using MCF-7 (and MDA-66, see below) cells has indicated that, as also reported by others, a concentration of 10 nM E2 was the optimal ligand concentration to be used for the highest level of pS2 gene induction in mammary cells cultured in vitro (results not shown, see [18,19]). Therefore, whenever we studied the effects of E2 we have added this ligand to cell culture medium at a 10 nM concentration.…”

Section: Ectopic Era Expression In Mda-mb-231 Upregulates Nis Expressionsupporting

confidence: 60%

“…3). Concerning the differences between cell lines, we must point out that, when compared to MCF-7, MDA-MB-231 (or MDA-66) cells are less differentiated, and it is known that the differentiation stage of breast cancer cell lines strongly affects the transcriptional activity of nuclear receptors [18]. In parallel to this, our results suggest that in addition to functionally expressed RARa and ERa, (an)other so far unidentified factor(s) are (is) essential for ligand-responsive expression of this gene in MDA-MB-231.…”

Section: Ectopic Era Expression In Mda-mb-231 Upregulates Nis Expressionmentioning

confidence: 99%

“…So far, transcriptional molecular elements and ligands that were hitherto shown to regulate NIS expression were identified in studies that were either carried out in experimental animals or in a rather differentiated mammary cell line, MCF-7 [1,3,5,6,[25][26][27][28][29][30][31]. Related with this, a particularity of our study is that we used a dedifferentiated tumor cell line such as MDA-MB-231 [18] in establishing the role of apo-ERa as a factor that activates NIS expression. Therefore, to our opinion, a less obvious but interesting implication of our data is the very early role of apo-ERa in activation of NIS transcription.…”

Section: Identification Of a Novel Non-canonical Ere In Nis Promotermentioning

confidence: 99%

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Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Alotaibi¹,

Yaman²,

Demirpençe³

et al. 2006

Biochemical and Biophysical Research Communications

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The function of sodium iodide symporter (Na + /I À symporter, or NIS) in mammary epithelial cells is essential for the accumulation of I À in milk; the newborn's first source of I À for thyroid hormone synthesis. Furthermore, increased mammary gland NIS expression has previously been shown in human breast cancer. Several hormones and factors including all-trans-retinoic acid (tRA) regulate the expression of NIS. In this study, using breast cancer cell lines, we established that tRA-responsive NIS expression is confined to estrogen receptor-a (ERa) positive cells and we investigated the role of ERa in the regulation of NIS expression. We showed that the suppression of endogenous ERa by RNA interference downregulates NIS expression in ERa positive mammary cells. Besides, in an ERa negative cell line, reintroduction of ERa resulted in the expression of NIS in a ligand-independent manner. We also identified a novel estrogen-responsive element in the promoter region of NIS that specifically binds ERa and mediates ERa-dependent activation of transcription. Our results indicate that unliganded ERa (apo-ERa) contributes to the regulation of NIS gene expression. In mammary gland lactocytes, sodium/iodide (Na + /I À ) symport via NIS is required to secrete I À in mother's milk [1]. I À in milk is used by the newborn in thyroid hormone biosynthesis, and thus it plays an essential role in post-natal development of skeletal muscles, nervous system, and lungs [2]. In vivo experiments in mice have previously demonstrated that in normal physiology, NIS expression is strictly linked to mammary development in gestation, and to lactation [1]. Non-lactating mammary gland tissue in female mice does not express NIS unless animals receive subcutaneous oxytocin treatments for three consecutive days. On the other hand, a similar treatment in ovariectomized mice is not sufficient for NIS upregulation. In these surgically treated animals, administration of 17-b-estradiol (E2) together with oxytocin is essential for functional expression of NIS. The fact that E2 treatment was only essential in ovariectomized animals, whereas lactogenic hormones were sufficient for functional NIS expression in surgically untreated mice, suggested that ovary functions and endogenous estrogens are essential in upregulating NIS expression [1]. Unlike in non-lactating mammary gland tissue, in transgenic mice bearing experimental breast cancers triggered by Erb-B2/neu and ras oncogenes, functional expression of NIS significantly increases [1]. In the same study, human breast cancer specimens were also analyzed, and an increased NIS expression was detected in human invasive breast cancer and ductal carcinoma in situ, as compared to no expression of NIS in healthy breast samples obtained from reductive mammoplasty operations [1].Recent studies with an ERa+ mammary cell line model, MCF-7, have led to the identification of additional hormones or ligands that control transcriptional regulation of NIS. In this cell line, the symporter gene was shown to be indu...

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Section: Ectopic Era Expression In Mda-mb-231 Upregulates Nis Expressionsupporting

confidence: 60%

Section: Ectopic Era Expression In Mda-mb-231 Upregulates Nis Expressionmentioning

confidence: 99%

Section: Identification Of a Novel Non-canonical Ere In Nis Promotermentioning

confidence: 99%

See 1 more Smart Citation

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Alotaibi¹,

Yaman²,

Demirpençe³

et al. 2006

Biochemical and Biophysical Research Communications

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show abstract

“…These observations can be correlated to the capacity of ERα, but not of ERβ, to recruit NCOA1 via its AF1 region in the presence of tamoxifen (Webb et al . 1998, Merot et al . 2004).…”

Section: Impact Of Ae-induced Erα Conformation On Cofactor Recruitmenmentioning

confidence: 99%

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Traboulsi

Ezzy

Gleason

et al. 2017

Journal of Molecular Endocrinology

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About 70% of breast tumors express estrogen receptor alpha (ERα), which mediates the proliferative effects of estrogens on breast epithelial cells, and are candidates for treatment with antiestrogens, steroidal or non-steroidal molecules designed to compete with estrogens and antagonize ERs. The variable patterns of activity of antiestrogens (AEs) in estrogen target tissues and the lack of systematic cross-resistance between different types of molecules have provided evidence for different mechanisms of action. AEs are typically classified as selective estrogen receptor modulators (SERMs), which display tissue-specific partial agonist activity (e.g. tamoxifen and raloxifene), or as pure AEs (e.g. fulvestrant), which enhance ERα post-translational modification by ubiquitin-like molecules and accelerate its proteasomal degradation. Characterization of second- and third-generation AEs, however, suggests the induction of diverse ERα structural conformations, resulting in variable degrees of receptor downregulation and different patterns of systemic properties in animal models and in the clinic.

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“…Specifically, only ϳ20% of all genes regulated through either ER isoform are regulated by both ER isoforms. The mechanism(s) of ER isoform-specific gene regulation are unknown; however because of the low level of homology between the ER␣ and ER␤ A/B (AF1) domains, differences in transcriptional activation may be largely due to AF1 function (30,31).In this study, we show that the RBBP1 gene, the protein product of which is involved in retinoblastoma-mediated suppression of cell proliferation, is differentially regulated by ER␣ and ER␤ in a U2OS model system. Using deletion and mutational analysis, we demonstrate that ER␣ utilizes a consensus Sp1 sequence, whereas ER␤ functions through both the Sp1 and a nearby ERE sequence.…”

mentioning

confidence: 99%

Estrogen Receptor Isoform-specific Regulation of the Retinoblastoma-binding Protein 1 (RBBP1) Gene

Monroe

Secreto

Hawse

et al. 2006

Journal of Biological Chemistry

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Estrogen (E2) is involved in mediating many important functions relevant to osteoblast biology through the actions of the estrogen receptors (ER) ␣ and ␤. To further understand the mechanisms of ER-specific regulation, we used microarray and reverse transcription-PCR analyses of E2-treated U2OS-ER␣ or -ER␤ cells and identified retinoblastoma-binding protein 1 (RBBP1) as a major E2-regulated gene. RBBP1 is a retinoblastoma cofactor involved in the control of osteoblastic proliferation. Although RBBP1 mRNA levels rapidly increased after 2 h of E2 treatment in both U2OS-ER-expressing lines, a sustained induction was only observed in U2OS-ER␣ cells. Examination of the RBBP1 genomic sequence revealed an ER response element and a Sp1 site located within the first intron. Chromatin immunoprecipitation analyses demonstrated that E2-dependent ER␣ binding to the intron 1 enhancer region was constitutive, whereas ER␤ binding was transient, consistent with the mRNA time course. Interestingly, transient transfection and receptor mutational studies revealed that RBBP1 induction by ER␣ only requires the Sp1 site, whereas ER␤ utilizes both the Sp1 and estrogen response elements binding sites for maximal E2-dependent activation. Stable U2OS transfectants containing a deletion of the ER␣ activation function 1 (AF1) resulted in a temporal mRNA induction profile similar to that of wild type ER␤. Further, overexpression and chromatin immunoprecipitation analyses also demonstrated that E2-dependent RBBP1 induction is SRC2-dependent for both ER isoforms. These results describe an E2-dependent, ER isoform-specific transcriptional activation of the RBBP1 gene, which in part, is explained by the differential activity of ER AF1 and enhancer element binding.The transcriptional effects of estrogens (e.g. 17␤-estradiol or E2) 2 are largely mediated by two related, but distinct, estrogen receptor (ER) isoforms ER␣ and ER␤ (1-7). The ERs are ligandinducible transcription factors that bind E2 through a C-terminally located ligand-binding domain (or E/F domain). The ER isoforms contain a centrally located and highly conserved DNA-binding domain (or C domain) that associates directly with estrogen response elements (ERE) or indirectly through protein tethering to AP1 or Sp1 (8, 9). Both ER␣ and ER␤ contain two activation functions (AF); a highly divergent N-terminal A/B (AF1) domain and a more conserved C-terminal E/F (AF2) domain that overlaps with the ligand-binding domain (10 -13). Activation of transcription is achieved through the recruitment of specific transcriptional coregulators resulting in chromatin remodeling and the recruitment of the basal transcriptional machinery (1, 9, 14 -16). Although coregulator recruitment and activation is largely mediated through AF2, the A/B domain (AF1) is known to bind the p160 and p300/CBP (CREB-binding protein) families of coregulators (16 -20) as well as p68/p72 (21, 22), steroid receptor RNA activator (23, 24), and MMS19 (25) proteins. Recent data from our laboratory (26, 27) and others (28, 29) have...

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The Relative Contribution Exerted by AF-1 and AF-2 Transactivation Functions in Estrogen Receptor α Transcriptional Activity Depends upon the Differentiation Stage of the Cell

Cited by 73 publications

References 51 publications

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene

Antiestrogens: structure-activity relationships and use in breast cancer treatment

Estrogen Receptor Isoform-specific Regulation of the Retinoblastoma-binding Protein 1 (RBBP1) Gene

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