ER-mediated Signaling Pathways Research Articles

ERECTA regulates seed size independently of its intracellular domain via MAPK-DA1-UBP15 signaling.

Seed size is determined by the coordinated growth of the embryo, endosperm, and integument. Growth of the integument is initiated by signal molecules released from the developing endosperm or embryo. Although recent studies have identified many components that regulate seed size by controlling integument growth, the upstream signals and the signal transduction pathway that activate these components after double fertilization are unclear. Here, we report that the receptor-like kinase ERECTA (ER) controls seed size by regulating outer integument cell proliferation in Arabidopsis thaliana. Seeds from er mutants were smaller, while those from ER-overexpressing plants were larger, than those of control plants. Different from its role in regulating the development of other organs, ER regulates seed size via a novel mechanism that is independent of its intracellular domain. Our genetic and biochemical data show that a MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) signaling pathway comprising MAPK-KINASE 4/5, MAPK 3/6 (MPK3/6), DA1, and UBIQUITIN SPECIFIC PROTEASE 15 (UBP15) functions downstream of ER and modulates seed size. MPK3/6 phosphorylation inactivates and destabilizes DA1 to increase the abundance of UBP15, promoting outer integument cell proliferation and increasing seed size. Our study illustrates a nearly completed ER-mediated signaling pathway that regulates seed size and will help uncover the mechanism that coordinates embryo, endosperm, and integument growth after double fertilization.

Heterogeneous Nuclear Ribonucleoprotein K Is Involved in the Estrogen-Signaling Pathway

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) has been found in the nucleus, cytoplasm, and mitochondria. It is implicated in chromatin remodeling, transcription, splicing, and translation processes. Although hnRNPK has reportedly been associated with poor prognosis in colon cancer patients, it is beneficial in gastric cancer as it inhibits cancer cell proliferation. Expression of hnRNPK in ER (Estrogen receptor) -positive/PR (Progesterone receptor) -positive breast cancer was higher than other subtypes; however, the biological functions of hnRNPK in the ER-mediated signaling pathway have not been identified. In this study, we investigated the functions of hnRNPK in the estrogen-signaling pathway. We initially evaluated hnRNPK expression upon treatment with estradiol (E2) and ICI 182,780 in ERα-positive breast cancer cell line MCF-7. This initial evaluation revealed that expression of hnRNPK was increased by E2 treatment but decreased by ICI 182,780 treatment. We further evaluated the effects of estrogen-signaling pathway in hnRNPK knockdown MCF-7 cells using siRNA, which revealed that hnRNPK knockdown decreased ERα expressions and ERα target gene TFF1 by E2 treatment. In addition, we examined the interaction between hnRNPK and ERα because hnRNPK has been reported to interact with several other proteins. These interactions were detected using immunoprecipitation and proximity ligation assay. We then immunolocalized hnRNPK in breast cancer and endometrial cancer. hnRNPK expression was significantly higher in ERα-positive cancer cells in both breast and endometrial cancers. In contrast, hnRNPK expression was significantly lower in Ki-67-positive breast cancer while being significantly higher in Ki-67-positive endometrial cancer. hnRNPK has been found to function differently, depending on the type of cancer (breast or endometrial) that it is expressed in. However, further studies are required to clarify the clinical significance of hnRNPK in breast and endometrial cancer patients.

Heterogeneous Nuclear Ribonucleoprotein K Is Involved in the Estrogen-Signaling Pathway in Breast Cancer

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) transcripts are abundant in estrogen receptor (ER)- or progesterone receptor (PR)-positive breast cancer. However, the biological functions of hnRNPK in the ER-mediated signaling pathway have remained largely unknown. Therefore, this study analyzes the functions of hnRNPK expression in the ER-mediated signaling pathway in breast cancer. We initially evaluated hnRNPK expression upon treatment with estradiol (E2) and ICI 182,780 in the ERα-positive breast carcinoma cell line MCF-7. The results revealed that E2 increased hnRNPK; however, hnRNPK expression was decreased with ICI 182,780 treatment, indicating estrogen dependency. We further evaluated the effects of hnRNPK knockdown in the ER-mediated signaling pathway in MCF-7 cells using small interfering RNAs. The results revealed that hnRNPK knockdown decreased ERα expression and ERα target gene pS2 by E2 treatment. As hnRNPK interacts with several other proteins, we explored the interaction between hnRNPK and ERα, which was demonstrated using immunoprecipitation and proximity ligation assay. Subsequently, we immunolocalized hnRNPK in patients with breast cancer, which revealed that hnRNPK immunoreactivity was significantly higher in ERα-positive carcinoma cells and significantly lower in Ki67-positive or proliferative carcinoma cells. These results indicated that hnRNPK directly interacted with ERα and was involved in the ER-mediated signaling pathway in breast carcinoma. Furthermore, hnRNPK expression could be an additional target of endocrine therapy in patients with ERα-positive breast cancer.

Chlorinated Polyfluoroalkylether Sulfonic Acids Exhibit Stronger Estrogenic Effects than Perfluorooctane Sulfonate by Activating Nuclear Estrogen Receptor Pathways.

Chlorinated polyfluoroalkylether sulfonic acids (Cl-PFESAs) have been shown to have potential thyroid hormone (TH) disruption effects. Here, we further investigated their estrogenic effects and underlying mechanisms. In vivo results revealed that exposure of zebrafish to Cl-PFESAs induced disorder of sex hormones during the early embryonic stages and caused histopathological lesions in the gonads of adult zebrafish relative to control groups. To find out whether the estrogen receptor is the molecular target of Cl-PFESAs, the binding interaction between Cl-PFESAs and ERs was investigated using a series of in vitro assays. We found that all tested chemicals could bind directly to ERs and exhibit relatively weak agonistic activity toward ERs, suggesting that the ER-mediated signaling pathway is directly involved in the estrogenic effects of Cl-PFESAs. The internal dose of 8:2 Cl-PFESA was significantly higher than the others, which explained why it obviously displayed an ER agonistic effect despite its weak ER binding affinity. Taken together, these results uncover that, in addition to the TH disruption effect, Cl-PFESAs might also cause estrogenic effects by activating ER pathways.

Luteolin-7-O-glucoside protects dopaminergic neurons by activating estrogen-receptor-mediated signaling pathway in MPTP-induced mice

BackgroundParkinson's disease (PD) is a neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in substantia nigra (SN). Accumulating evidences implicate the beneficial role of estrogen in the therapy of PD. MethodsIn the present study, the protective function of luteolin-7-O-glucoside (LUT-7G), a natural flavonoid, was investigated in 1-methyl-4-phenylpyridinium (MPP+) treated SH-SY5Y cells and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced mice. ResultsPre-treatment of LUT-7G increased the viability and reduced the apoptosis of SH-SY5Y cells treated by MPP+. At molecular level, the Bcl-2/Bax ratio was increased, while the expression of cleaved caspase 3 was markedly lessened. Moreover, LUT-7G increased the expression of estrogen receptor (ER), ERα and ERβ, and enhanced the activation of ERK1/2/STAT3/c-Fos that could be abolished by ER antagonists. Furthermore, in vivo experiment indicated that pre-treatment of LUT-7G improved the bradykinesia, and enhanced the muscle strength as well as the balancing capacity of mice treated with MPTP. And LUT-7G prevented the injury of TH positive cells in substantia nigra and increased TH positive nerve fibers in striatum. In addition, pre-treatment of LUT-7G also significantly diminished the MPTP-induced gliosis in substantia nigra. ConclusionsLUT-7G effectively protected dopaminergic neurons against MPP+ or MPTP-induced toxicity, probably by activating the ER-mediated signaling pathway. Our findings explore the therapeutic potential of LUT-7G for PD therapy.

Abstract 4755: Estrogen receptor mediates novel mechanisms of estrogen-induced growth and tamoxifen resistance in invasive lobular carcinoma

Abstract Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer representing ∼10% of newly diagnosed breast tumors. Over 90% of ILC cases are ER-positive, however, endocrine response and estrogen signaling are not well described in ILC. Retrospective analyses suggest that ILC patients treated with endocrine therapy have poorer outcomes than invasive ductal carcinoma (IDC) patients with similar biomarkers, and that ILC patients may not benefit from adjuvant tamoxifen. Additionally, we have recently identified ILC-specific ER-target genes and de novo tamoxifen resistance driven by ER in ILC model systems. Based on these observations, we hypothesize that ILC-specific signaling pathways driven by ER mediate growth and endocrine resistance in ILC cells. We focused on three putative mechanisms of endocrine response and resistance in ILC cells. First, we investigated the role of the Wnt signaling protein WNT4 in driving E2-induced growth. E2 induced ER binding at the WNT4 promoter and up-regulated expression specifically in ILC cells (versus IDC cells). As WNT4 has also been previously implicated in normal mammary gland growth and development, we hypothesize that ER-driven WNT4 expression of mediates E2-induced growth of ILC cells. Second, we investigated the role of the transcriptional repressor SNAI1 in ER-mediated gene expression and tamoxifen-resistance. SNAI1 gene expression was induced by both E2 and tamoxifen specifically in ILC cells, which paralleled unique patterns of E2-mediated gene repression in ILC cells. Thus, SNAI1 may mediate E2-driven gene repression and tamoxifen resistance. Third, our prior identification of ILC-specific ER-target genes and ER-mediated tamoxifen resistance suggested that novel co-factors may associate with ER in ILC. We hypothesize that identification of these co-factors would provide novel targets for therapy in ILC. Cell lines MDA MB 134VI and SUM44PE are used as in vitro models of ILC versus MCF-7 and T47D as models of IDC. siRNA-mediated knockdown of gene expression is utilized to assess the function of WNT4 and SNAI1. Cell proliferation and ER-target gene expression are assessed in both ILC and IDC models following knockdown. To identify novel ER co-factors in ILC, we co-immunoprecipitate ER with associated factors, and identify bound proteins by mass spectrometry. Preliminary experiments have demonstrated that knockdown of either WNT4 or SNAI1 can suppress the growth of ILC cells, and that this effect is specific to ILC cells. Additionally, Co-IP/mass spec identifies co-factors that are specifically associated with ER in ILC cells. These observations suggest that unique ER-mediated signaling pathways drive endocrine response and resistance in ILC cells, and that further understanding of these pathways may present novel therapeutic targets in ILC. Citation Format: Matthew J. Sikora, Amir Bahreini, Steffi Oesterreich. Estrogen receptor mediates novel mechanisms of estrogen-induced growth and tamoxifen resistance in invasive lobular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4755. doi:10.1158/1538-7445.AM2014-4755

4-tert-Octylphenol stimulates the expression of cathepsins in human breast cancer cells and xenografted breast tumors of a mouse model via an estrogen receptor-mediated signaling pathway

Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERα. In conclusion, our findings suggest that OP at 10−6M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of cathepsin B. These effects of mouse model resulted in an increased potential for metastasis in breast cancer. Taken together, we determined that OP can adversely affect human health by promoting cancer proliferation and metastasis through the amplification of cathepsins B and D via the ER-mediated signaling pathway.

Dual roles of estrogen metabolism in mammary carcinogenesis

A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review.

Bisphenol-A rapidly promotes dynamic changes in hippocampal dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDA receptor subunit NR2B

Bisphenol-A (BPA) is known to be a potent endocrine disrupter. Evidence is emerging that estrogen exerts a rapid influence on hippocampal synaptic plasticity and the dendritic spine density, which requires activation of NMDA receptors. In the present study, we investigated the effects of BPA (ranging from 1 to 1000 nM), focusing on the rapid dynamic changes in dendritic filopodia and the expressions of estrogen receptor (ER) β and NMDA receptor, as well as the phosphorylation of NMDA receptor subunit NR2B in the cultured hippocampal neurons. A specific ER antagonist ICI 182,780 was used to examine the potential involvement of ERs. The results demonstrated that exposure to BPA (ranging from 10 to 1000 nM) for 30 min rapidly enhanced the motility and the density of dendritic filopodia in the cultured hippocampal neurons, as well as the phosphorylation of NR2B (pNR2B), though the expressions of NMDA receptor subunits NR1, NR2B, and ERβ were not changed. The antagonist of ERs completely inhibited the BPA-induced increases in the filopodial motility and the number of filopodia extending from dendrites. The increased pNR2B induced by BPA (100 nM) was also completely eliminated. Furthermore, BPA attenuated the effects of 17β-estradiol (17β-E 2) on the dendritic filopodia outgrowth and the expression of pNR2B when BPA was co-treated with 17β-E 2. The present results suggest that BPA, like 17β-E 2, rapidly results in the enhanced motility and density of dendritic filopodia in the cultured hippocampal neurons with the concomitant activation of NMDA receptor subunit NR2B via an ER-mediated signaling pathway. Meanwhile, BPA suppressed the enhancement effects of 17β-E 2 when it coexists with 17β-E 2. These results provided important evidence suggesting the neurotoxicity of the low levels of BPA during the early postnatal development of the brain.

Estrogen Receptors are Involved in Xenoestrogen Induction of Growth Hormone in the Rat Pituitary Gland

Growth hormone (GH) plays a pivotal role in the regulation of growth, development and body composition. In order to provide new insights into estrogenic endocrine disruptor (ED) activities in the pituitary gland and the potential role played by estrogen receptors (ERs) in mediating their effects in vivo, we examined GH expression in the pituitary gland of an immature rat model. At postnatal day 14, immature rats were treated with various doses of 4-tert-octylphenol (OP), p-nonylphenol (NP) and bisphenol A (BPA), and the GH mRNA and protein expression levels were analyzed by real-time quantitative PCR and western blot/immunohistochemistry (IHC), respectively. An anti-estrogen (ICI 182780) was used to examine the potential involvement of ERs in ED-induced GH expression during critical windows of development. GH mRNA expression increased significantly 48 h after treatment with a high dose (600 mg/kg body weight [BW]) of OP or NP. However, this induction was abolished completely by co-treatment with ICI 182780. No significant difference in GH mRNA expression was observed following treatment with BPA or co-treatment of BPA with the anti-estrogen. Exposure to high doses (600 mg/kg BW) of these EDs significantly enhanced GH protein expression in the rat pituitary gland, whereas pretreatment with ICI 182780 markedly reduced this expression. Taken together, we have demonstrated for the first time that in vivo exposure to EDs can induce GH mRNA and protein expression in the rat pituitary gland and that their activities may involve an ER-mediated signaling pathway. These results may provide critical evidence for ED-induced dysregulation of pituitary GH expression and thus may be important for elucidating the potential impacts of EDs in altered body growth and development and for predicting the health risks of ED exposure in humans and wildlife.

Different biological effect of estrogen receptor-related receptor α in estrogen receptor-positive and -negative endometrial carcinoma

Estrogen receptor-related receptor α (ERRα) has been identified as a nuclear transfactor closely related to estrogen receptor α (ERα). ERRα interferes with ER-mediated signaling pathways through competition with ERα for the common DNA sites and coregulators. Thus, it may participate in the tumorigenesis of estrogen-related cancers. To elucidate the roles of ERRα in endometrial carcinogenesis and the crosstalk between ERα and ERRα, endometrial carcinoma Ishikawa and HEC-IA cells were treated with different concentrations of 17β-E2 and/or the pure anti-estrogen drug ICI182,780. Using semi-quantitative RT-PCR and Western blot analysis, we found that 17β-E2 down-regulated the expression of ERRα in ER-positive Ishikawa cells, while up-regulating the expression of ERRα in ER-negative HEC-IA cells. Down-regulation in Ishikawa cells was furthermore found to be largely abrogated by ICI182,780. Additionally, we constructed endometrial carcinoma cell lines with overexpression of ERRα by stable transfection, renaming these Ishikawa/ERRα and HEC-IA/ERRα, respectively. To investigate the effect of ERRα overexpression on the biological behavior of the cells, MTT assay and flow cytometry analysis were performed in the constructed cell lines. In ER-positive Ishikawa cells, the overexpression of ERRα inhibited cell growth in the presence of 17β-E2, an inhibitory effect that might be due to a G0-G1 cell cycle arrest. In contrast, overexpression of ERRα stimulated cell proliferation in ER-negative HEC-IA cells independently of 17β-E2. This accelerated action was associated with changes in cell cycle distribution. Our study demonstrates that, in addition to ER, ERRα seems to be an important regulator in endometrial carcinogenesis, playing different roles in estrogen-dependent and -independent endometrial carcinomas. ERRα might modulate the ER-mediated pathways via interference with ERα transcription in endometrial carcinoma cells.

Tetrabromodiphenyl Ether (BDE 47) Evokes Estrogenicity and Calbindin-D9k Expression through an Estrogen Receptor-Mediated Pathway in the Uterus of Immature Rats

Polybrominated diphenyl ethers (PBDEs), a class of organic brominated flame retardants, have been increasing in the environment and in the tissues and milk of animals, including humans. To date, 209 PBDE congeners have been reported. Among these, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) is the dominant congener found in humans and animals. A number of studies have suggested that BDE 47 possesses the potential to disrupt the endocrine system, as well as reproductive functions. This suggests that BDE 47 may act as a developmental neurotoxin and endocrine disruptor. In this study, we employed immature rats as a developmental model to examine the potential involvement of BDE 47 in the induction of calbindin-D9k (CaBP-9k), which is a novel biomarker for screening estrogenic compounds. Beginning on postnatal day 16, BDE 47 was administered to immature rats in a dose- and time-dependent manner for 3 days. The biological effects of BDE 47 on the induction of CaBP-9k mRNA and protein were examined by semiquantitative RT-PCR and western blotting, respectively. In addition, the physiological role of the estrogen receptor (ER) in BDE 47-induced CaBP-9k expression was examined in vivo. Treatment with a high dose of BDE 47 (200 mg/kg body weight [BW]/day) resulted in a significant increase in CaBP-9k mRNA and protein 24 h after injection, whereas a modest increase was observed with low and medium doses (50 and 100 mg/kg BW/day). Additionally, treatment with the high dose of BDE 47 induced a clear uterotrophic response. Cotreatment with ICI 182,780, an ER antagonist, completely reversed the BDE 47-induced increases in uterine wet weight and CaBP-9k mRNA and protein. Taken together, these results demonstrate that BDE 47 exposure results in increases in CaBP-9k mRNA and protein in the uteri of immature rats. The biochemical pathway for BDE 47-induced activity may involve the ER-mediated signaling pathway. These results provide new insights into the estrogenic effects of BDE 47 at a critical developmental stage of the female reproductive system.

Estrogen Signaling Multiple Pathways to Impact Gene Transcription

Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17beta-estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-kappaB (NF-kappaB) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge.

Inhibitory Cross-talk between Estrogen Receptor (ER) and Constitutively Activated Androstane Receptor (CAR): CAR INHIBITS ER-MEDIATED SIGNALING PATHWAY BY SQUELCHING p160 COACTIVATORS

Estrogen receptor (ER) activity can be modulated by the action of other nuclear receptors. To study whether ER activity is altered by orphan nuclear receptors that mediate the cellular response to xenobiotics, cross-talk between ER and constitutive androstane receptor (CAR), steroid and xenobiotic receptor, or peroxisome proliferator-activated receptor gamma was examined in HepG2 cells. Of these receptors, CAR substantially inhibited ER-mediated transcriptional activity of the vitellogenin B1 promoter as well as a synthetic estrogen responsive element (ERE)-containing promoter. Treatment with an agonist of CAR, 1,4-bis-(2-(3,5-dichloropyridoxyl))benzene, potentiated CAR-mediated transcriptional repression. In contrast, an antagonist of CAR, androstenol, alleviated the repression effect. Although CAR interacted with the ER in solution, CAR did not interact with the ER bound to the ERE. CAR/retinoid X receptor bound to the ERE but with much lower affinity than ER. Incremental amounts of CAR elicited a progressive reduction of the ER activity induced by the p160 coactivator glucocorticoid receptor interacting protein 1 (GRIP-1). In turn, increasing amounts of GRIP-1 progressively reversed the depression of ER activity by CAR. An agonist or antagonist of CAR potentiated or alleviated, respectively, the CAR-mediated repression of the GRIP-1-enhanced ER activity, which is consistent with the ability of theses ligands to increase or decrease, respectively, the interaction of CAR with GRIP-1. A CAR mutant that did not interact with GRIP-1 did not inhibit ER-mediated transactivation. Our data demonstrate that xenobiotic nuclear receptor CAR antagonizes ER-mediated transcriptional activity by squelching limiting amounts of p160 coactivator and imply that xenobiotics may influence ER function of female reproductive physiology, cell differentiation, tumorigenesis, and lipid metabolism.

Interplay between liganded and orphan nuclear receptors controls reproductive pathways

Nuclear receptors are transcription factors that belong to an evolutionary ancient superfamily. These proteins, which are even present in primitive metazoans, are implicated in all levels of cell fate: proliferation, differentiation, and apoptosis. Some of these nuclear receptors behave as ligand-inducible transcription factors, as they have acquired during evolution the ability to bind ligands. This is the case for some proteins that recognize small hydrophobic signaling molecules, and particularly the estrogen receptor (ER or NR3A1), which regulates the target gene's transcription rate under estrogen binding. It is now known that the ER alone regulates the transcription of many genes, such as those implicated in reproductive functions. However, this ER-mediated signaling pathway could be modulated by other transcription factors. Our work has established that two other orphan nuclear receptors (SF-1 or NR5A1 and the COUP-TFs, NR2F1 and NR2F2) can enhance two ER-regulated genes implicated in salmonid reproductive functions: the ER gene itself, and the sGTHIIbeta gene. Moreover, some xenoestrogens could disturb these regulations. Therefore, our data contribute to the concept that interplay between nuclear receptors is an important event for the transcriptional regulation of genes controlling cellular functions.

Interplay between liganded and orphan nuclear receptors controls reproductive pathways

Nuclear receptors are transcription factors that belong to an evolutionary ancient superfamily. These proteins, which are even present in primitive metazoans, are implicated in all levels of cell fate: proliferation, differentiation, and apoptosis. Some of these nuclear receptors behave as ligand-inducible transcription factors, as they have acquired during evolution the ability to bind ligands. This is the case for some proteins that recognize small hydrophobic signaling molecules, and particularly the estrogen receptor (ER or NR3A1), which regulates the target gene's transcription rate under estrogen binding. It is now known that the ER alone regulates the transcription of many genes, such as those implicated in reproductive functions. However, this ER-mediated signaling pathway could be modulated by other transcription factors. Our work has established that two other orphan nuclear receptors (SF-1 or NR5A1 and the COUP-TFs, NR2F1 and NR2F2) can enhance two ER-regulated genes implicated in salmonid reproductive functions: the ER gene itself, and the sGTHIIbeta gene. Moreover, some xenoestrogens could disturb these regulations. Therefore, our data contribute to the concept that interplay between nuclear receptors is an important event for the transcriptional regulation of genes controlling cellular functions.