Thyroid Hormone Receptor alpha-1 Directly Controls Transcription of the beta-Catenin Gene in Intestinal Epithelial Cells

Thyroid hormones, T3 and T4, are known regulators of intestine development. The best characterized example is the remodeling of the gastrointestinal tract during amphibian metamorphosis. Thyroid hormones act via nuclear receptors, the TRs, which are T3-dependent transcription factors. We previously showed that intestinal epithelial cell proliferation is controlled by thyroid hormones and the TRalpha gene. To analyze the mechanisms responsible, we studied the expression of genes belonging to and/or activated by the Wnt/beta-catenin pathway, a major actor in the control of physiological and pathological epithelial proliferation in the intestine. We show that T3-TR1 controls the transcription of the beta-catenin gene in an epithelial cell-autonomous way. This is parallel to positive regulation of proliferation-controlling genes such as type D cyclins and c-myc, known targets of the Wnt/-beta-catenin. In addition, we show that the regulation of the beta-catenin gene is direct, as TR binds in vitro and in chromatin in vivo to a specific thyroid hormone-responsive element present in intron 1 of this gene. This is the first report concerning in vivo transcriptional control of the beta-catenin gene. As Wnt/beta-catenin plays a crucial role in intestinal tumorigenesis, our observations open a new perspective on the study of TRs as potential tumor inducers

Critical role of hnRNP A1 in HTLV-1 replication in human transformed T lymphocytes

BACKGROUND: In this study, we have examined the role of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) in viral gene expression in T lymphocytes transformed by HTLV-1. RESULTS: We have previously observed that hnRNP A1 (A1) down-modulates the post transcriptional activity of Rex protein of HTLV-1. Here, we tested whether the ectopic expression of a dominant negative mutant (NLS-A1-HA) defective in shuttling activity or knockdown of the hnRNPA1 gene using RNA interference could inhibit Rex-mediated export of viral mRNAs in HTLV-1 producing C91PL T-cells. We show that the expression of NLS-A1-HA does not modify the export of Rex-dependent viral mRNAs. Conversely, inhibiting A1 expression in C91PL cells by RNA interference provoked an increase in the Rex-dependent export of unspliced and singly spliced mRNAs. Surprisingly, we also observed a significant increase in proviral transcription and an accumulation of unspliced mRNAs, suggesting that the splicing process was affected. Finally, A1 knockdown in C91PL cells increased viral production by these cells. Thus, hnRNP A1 is implicated in the modulation of the level of HTLV-1 gene expression in T cells transformed by this human retrovirus. CONCLUSIONS: These observations provide an insight into a new cellular control of HTLV-1 replication and suggest that hnRNP A1 is likely part of the regulatory mechanisms of the life cycle of this human retrovirus in T cells

Etude du rôle du récepteur aux hormones thyroïdiennes TRalpha 1 dans la prolifération normale et pathologique de l'épithélium intestinal

The intestinal epithelium is a perpetually renewing tissue. This renewal implies adult stem cells, localized at the basis of the villi in the intestinal crypts, that give birth to proliferative progenitors. The control of the proliferation of stem cells and progenitors is a key factor for maintaining the homeostasis of the tissue. The main signalling pathway implied in the control of the epithelial cell proliferation is the Wnt pathway.The thyroid hormones (TH) act through nuclear receptors. Previous work led in the lab has showed that TRα1 is the TH receptor that controls the proliferation of the intestinal crypt cells.During my PhD, I have showed that TRα1 and TH are important for the expression and the activation of several partners of the Wnt pathway, as in the initiation of hyperproliferative pathologies in mouse intestine.L'épithélium intestinal est un tissu en perpétuel renouvellement. Ceci met en jeu des cellules souches adultes, localisées à la base des villosités dans les cryptes intestinales, qui donnent naissance à des progéniteurs prolifératifs. Le contrôle de la prolifération des cellules souches et des progéniteurs est un facteur clé du maintient de l'homéostasie du tissu. La principale voie de signalisation qui régule cette prolifération est la voie Wnt. Les hormones thyroïdiennes (HT) agissent par l'intermédiaire de récepteurs nucléaires. Des travaux menés précédemment dans l'équipe ont montrés que TRα1 est le récepteur aux HT qui contrôle la prolifération des cellules des cryptes intestinales.Durant mon travail de thèse j'ai montré l'importance de TRα1 et des HT dans le contrôle de l'expression de différents partenaires de la voie Wnt, ainsi que dans l'initiation de pathologiques hyperprolifératives de l'intestin chez la souris

Etude du rôle du récepteur aux hormones thyroïdiennes TRalpha 1 dans la prolifération normale et pathologique de l épithélium intestinal

L épithélium intestinal est un tissu en perpétuel renouvellement. Ceci met en jeu des cellules souches adultes, localisées à la base des villosités dans les cryptes intestinales, qui donnent naissance à des progéniteurs prolifératifs. Le contrôle de la prolifération des cellules souches et des progéniteurs est un facteur clé du maintient de l homéostasie du tissu. La principale voie de signalisation qui régule cette prolifération est la voie Wnt. Les hormones thyroïdiennes (HT) agissent par l intermédiaire de récepteurs nucléaires. Des travaux menés précédemment dans l équipe ont montrés que TRa1 est le récepteur aux HT qui contrôle la prolifération des cellules des cryptes intestinales. Durant mon travail de thèse j ai montré l importance de TRa1 et des HT dans le contrôle de l expression de différents partenaires de la voie Wnt, ainsi que dans l initiation de pathologiques hyperprolifératives de l intestin chez la souris.The intestinal epithelium is a perpetually renewing tissue. This renewal implies adult stem cells, localized at the basis of the villi in the intestinal crypts, that give birth to proliferative progenitors. The control of the proliferation of stem cells and progenitors is a key factor for maintaining the homeostasis of the tissue. The main signalling pathway implied in the control of the epithelial cell proliferation is the Wnt pathway. The thyroid hormones (TH) act through nuclear receptors. Previous work led in the lab has showed that TRa1 is the TH receptor that controls the proliferation of the intestinal crypt cells. During my PhD, I have showed that TRa1 and TH are important for the expression and the activation of several partners of the Wnt pathway, as in the initiation of hyperproliferative pathologies in mouse intestine.LYON-ENS Sciences (693872304) / SudocSudocFranceF