RESUMEN
Spermatogenesis is a complex process involving cell proliferation, differentiation, and apoptosis. Fibroblast growth factor 2 (FGF-2) is involved in testicular function, but its role in spermatogenesis has not been fully documented. The control of FGF-2 expression particularly occurs at the translational level, by an internal ribosome entry site (IRES)-dependent mechanism driving the use of alternative initiation codons. To study IRES activity regulation in vivo, we have developed transgenic mice expressing a bicistronic construct coding for two luciferase genes. Here, we show that the FGF-2 IRES is age-dependently activated in mouse testis, whereas EMCV and c-myc IRESs are not. Real-time PCR confirms that this regulation is translational. By using immunohistological techniques, we demonstrate that FGF-2 IRES stimulation occurs in adult, but not in immature, type-A spermatogonias. This is correlated with activation of endogenous FGF-2 expression in spermatogonia; whereas FGF-2 mRNA transcription is known to decrease in adult testis. Interestingly, the FGF-2 IRES activation is triggered by testosterone and is partially inhibited by siRNA directed against the androgen receptor. Two-dimensional analysis of proteins bound to the FGF-2 mRNA 5'UTR after UV cross-linking reveals that testosterone treatment correlates with the binding of several proteins. These data suggest a paracrine loop where IRES-dependent FGF-2 expression, stimulated by Sertoli cells in response to testosterone produced by Leydig cells, would in turn activate Leydig function and testosterone production. In addition, nuclear FGF-2 isoforms could be involved in an intracrine function of FGF-2 in the start of spermatogenesis, mitosis, or meiosis initiation. This report demonstrates that mRNA translation regulation by an IRES-dependent mechanism participates in a physiological process.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/fisiología , Células Intersticiales del Testículo/fisiología , Biosíntesis de Proteínas , ARN Mensajero/genética , Secuencias Reguladoras de Ácidos Nucleicos , Células de Sertoli/fisiología , Espermatogénesis/fisiología , Testículo/fisiología , Testosterona/fisiología , Regiones no Traducidas 5' , Factores de Edad , Antagonistas de Receptores Androgénicos , Animales , Codón , Factor 2 de Crecimiento de Fibroblastos/biosíntesis , Factor 2 de Crecimiento de Fibroblastos/genética , Genes Reporteros , Genes Sintéticos , Luciferasas de Renilla/genética , Masculino , Meiosis , Ratones , Ratones Transgénicos , Mitosis , Comunicación Paracrina , Iniciación de la Cadena Peptídica Traduccional/fisiología , Isoformas de Proteínas/fisiología , ARN Mensajero/efectos de la radiación , ARN Interferente Pequeño/farmacología , Receptores Androgénicos/genética , Proteínas Recombinantes de Fusión/fisiología , Ribosomas/metabolismo , Testículo/crecimiento & desarrollo , Testículo/metabolismo , Testosterona/metabolismo , Testosterona/farmacología , Rayos UltravioletaRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief as it contains inappropriately manipulated images in Figure 7B. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter, and apologies are offered to the readers of the journal that this problem was not detected during the submission process.
RESUMEN
Neurological diseases comprise a group of heterogeneous disorders characterized by progressive brain dysfunction and cell death. In the next years, these diseases are expected to constitute a world-wide health problem. Because excitotoxicity and oxidative stress are involved in neurodegenerative diseases, it becomes relevant to describe pharmacological therapies designed to activate endogenous cytoprotective systems. Activation of transcription factor Nrf2 stimulates cytoprotective vitagenes involved in antioxidant defense. In this work, we investigated the ability of the antioxidant curcumin to induce transcription factor Nrf2 in a neurodegenerative model induced by quinolinic acid in rats. Animals were administered with curcumin (400 mg/kg, p.o.) for 10 days, and then intrastriatally infused with quinolinic acid (240 nmol) on day 10 of treatment. Curcumin prevented rotation behavior (6 days post-lesion), striatal morphological alterations (7 days post-lesion) and neurodegeneration (1 and 3 days post-lesion) induced by quinolinic acid. Curcumin also reduced quinolinic acid-induced oxidative stress (measured as protein carbonyl content) at 6 h post-lesion. The protective effects of curcumin were associated to its ability to prevent the quinolinic acid-induced decrease of striatal intra-nuclear Nrf2 levels (30 and 120 min post-lesion), and total superoxide dismutase and glutathione peroxidase activities (1 day post-lesion). Therefore, results of this study support the concept that neuroprotection induced by curcumin is associated with its ability to activate the Nrf2 cytoprotective pathway and to increase the total superoxide dismutase and glutathione peroxidase activities.