RESUMEN
Bisphenol A (BPA) is an endocrine disruptor that displays estrogenic activity. Several reports suggest that BPA may have estrogen receptor-independent effects. In zebrafish, 50 µM BPA exposure induces otic vesicle abnormalities, including otolith aggregation. The purpose of this study was to test if BPA action was mediated in vivo during zebrafish development by the orphan nuclear estrogen related receptor (ERR) γ. Combining pharmacological and functional approaches, we demonstrate that the zebrafish ERRγ mediates BPA-induced malformations in otoliths. Using different bisphenol derivatives, we show that different compounds can induce a similar otolith phenotype than BPA and that the binding affinity of these derivatives to the zebrafish ERRγ correlates with their ability to induce otolith malformations. Morpholino knockdown of ERRγ function suppresses the BPA effect on otoliths whereas overexpression of ERRγ led to a BPA-like otolith phenotype. Moreover, a subphenotypical dose of BPA (1 µM) combined with ERRγ overexpression led to a full-dose (50 µM) BPA otolith phenotype. We therefore conclude that ERRγ mediates the otic vesicle phenotype generated by BPA. Our results suggest that the range of pathways perturbed by this compound and its potential harmful effect are larger than expected.-Tohmé, M., Prud'homme, S. M., Boulahtouf, A., Samarut, E., Brunet, F., Bernard, L., Bourguet, W., Gibert, Y., Balaguer, P., Laudet, V. Estrogen-related receptor γ is an in vivo receptor of bisphenol A.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Fenoles/farmacología , Unión Proteica/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Pez Cebra/metabolismo , Animales , Membrana Otolítica/efectos de los fármacos , Membrana Otolítica/metabolismoRESUMEN
Despite anecdotal reports of HIV-1 co-infections and super-infections, few large-scale prevalence studies are available on multiple HIV-1 infection. We systematically searched for HIV-1 co-infections by means of a heteroduplex mobility assay in 660 HIV-1 seroconverters from the two ANRS SEROCO and PRIMO cohorts. Our results strongly suggest that HIV-1 co-infection remains a rare phenomenon in HIV-1 seroconverters infected in France between 1986 and 2004.
Asunto(s)
Seropositividad para VIH/virología , VIH-1/clasificación , Estudios de Cohortes , Francia/epidemiología , Seropositividad para VIH/epidemiología , VIH-1/genética , VIH-1/aislamiento & purificación , Análisis Heterodúplex , Humanos , PrevalenciaRESUMEN
In hormone-dependent tissues such as breast and ovary, tumorigenesis is associated with an altered expression ratio between the two estrogen receptor (ER) subtypes. In this study, we investigated the effects of ERß ectopic expression on 17ß-estradiol (E2)-induced transactivation and cell proliferation in ERα-positive BG1 ovarian cancer cells. As expected, ERß expression strongly decreased the mitogenic effect of E2, significantly reduced E2-dependent transcriptional responses (both on a stably integrated estrogen response element [ERE] reporter gene and on E2-induced mRNAs), and strongly enhanced the formation of ER heterodimers as evidenced by chromatin immunoprecipitation analysis. Inhibition by the ERα-selective ligand propyl pyrazole triol was less marked than with the pan-agonist (E2) or the ERß-selective (8ß-vinyl-estradiol) ligands, indicating that ERß activation reinforced the inhibitory effects of ERß. Interestingly, in E2-stimulated BG1 cells, ERß was more efficient than ERα to regulate the expression of receptor-interacting protein 140 (RIP140), a major ERα transcriptional corepressor. In addition, we found that the RIP140 protein interacted better with ERß than with ERα (both in vitro and in intact cells by fluorescence cross-correlation spectroscopy). Moreover, RIP140 recruitment on the stably integrated reporter ERE was increased upon ERß overexpression, and ERß activity was more sensitive to repression by RIP140. Finally, small interfering RNA-mediated knockdown of RIP140 expression abolished the repressive effect exerted by activated ERß on the regulation of ERE-controlled transcription by estrogens. Altogether, these data demonstrate the inhibitory effects of ERß on estrogen signaling in ovarian cancer cells and the key role that RIP140 plays in this phenomenon.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Receptor beta de Estrógeno/metabolismo , Estrógenos/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Transducción de Señal , Animales , Células COS , Línea Celular Tumoral , Proliferación Celular , Chlorocebus aethiops , ADN de Neoplasias/metabolismo , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Reporteros , Humanos , Ligandos , Proteína de Interacción con Receptores Nucleares 1 , Neoplasias Ováricas/genética , Unión Proteica/genética , Activación Transcripcional/genéticaRESUMEN
The human pregnane X receptor (PXR) is a ligand-regulated transcription factor belonging to the nuclear receptor superfamily. PXR is activated by a large, structurally diverse, set of endogenous and xenobiotic compounds and coordinates the expression of genes central to metabolism and excretion of potentially harmful chemicals and therapeutic drugs in humans. Walrycin A is a novel antibacterial compound targeting the WalK/WalR two-component signal transduction system of Gram (+) bacteria. Here, we report that, in hepatoma cells, walrycin A potently activates a gene set known to be regulated by the xenobiotic sensor PXR. Walrycin A was as efficient as the reference PXR agonist rifampicin to activate PXR in a transactivation assay at noncytotoxic concentrations. Using a limited proteolysis assay, we show that walrycin A induces conformational changes at a concentration which correlates with walrycin A ability to enhance the expression of prototypic target genes, suggesting that walrycin A interacts with PXR. The activation of the canonical human PXR target gene CYP3A4 by walrycin A is dose and PXR dependent. Finally, in silico docking experiments suggest that the walrycin A oxidation product Russig's blue is the actual ligand for PXR. Taken together, these results identify walrycin A as a novel human PXR activator.