Publications (184) View all
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Article: Direct cooperation between androgen receptor and E2F1 reveals a common regulation mechanism for androgen-responsive genes in prostate cells.
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ABSTRACT: We have studied the regulation of ATAD2 gene expression by androgens in prostate cells. ATAD2 is a coactivator of the androgen receptor (AR) and the MYC protein. We showed that ATAD2 expression is directly regulated by AR via an AR binding sequence (ARBS) located in the distal enhancer of its regulatory region. The gene is also regulated by the E2F1 transcription factor. Using knockdown and chromatin immunoprecipitation technique approaches, we could demonstrate that AR and E2F1 functionally collaborate and physically interact between each other. From the analysis of chromatin conformation, we conclude that this cooperation results from a chromatin looping over the ATAD2 promoter region between the ARBS and E2F1 binding site in an androgen-dependent manner. Furthermore, we could show that several genes overexpressed in prostate cancer and potentially involved in several aspects of tumor development have an ARBS and an E2F1 binding site in their regulatory regions and exhibit the same mechanism of regulation by both transcription factors as ATAD2.Molecular Endocrinology 07/2012; 26(9):1531-41. · 4.54 Impact Factor -
Article: The endogenous retrovirus ENS-1 provides active binding sites for transcription factors in embryonic stem cells that specify extra embryonic tissue.
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ABSTRACT: Long terminal repeats (LTR) from endogenous retroviruses (ERV) are source of binding sites for transcription factors which affect the host regulatory networks in different cell types, including pluripotent cells. The embryonic epiblast is made of pluripotent cells that are subjected to opposite transcriptional regulatory networks to give rise to distinct embryonic and extraembryonic lineages. To assess the transcriptional contribution of ERV to early developmental processes, we have characterized in vitro and in vivo the regulation of ENS-1, a host adopted and developmentally regulated ERV that is expressed in chick embryonic stem cells. We show that Ens-1 LTR activity is controlled by two transcriptional pathways that drive pluripotent cells to alternative developmental fates. Indeed, both Nanog that maintains pluripotency and Gata4 that induces differentiation toward extraembryonic endoderm independently activate the LTR. Ets coactivators are required to support Gata factors' activity thus preventing inappropriate activation before epigenetic silencing occurs during differentiation. Consistent with their expression patterns during chick embryonic development, Gata4, Nanog and Ets1 are recruited on the LTR in embryonic stem cells; in the epiblast the complementary expression of Nanog and Gata/Ets correlates with the Ens-1 gene expression pattern; and Ens-1 transcripts are also detected in the hypoblast, an extraembryonic tissue expressing Gata4 and Ets2, but not Nanog. Accordingly, over expression of Gata4 in embryos induces an ectopic expression of Ens-1. Our results show that Ens-1 LTR have co-opted conditions required for the emergence of extraembryonic tissues from pluripotent epiblasts cells. By providing pluripotent cells with intact binding sites for Gata, Nanog, or both, Ens-1 LTR may promote distinct transcriptional networks in embryonic stem cells subpopulations and prime the separation between embryonic and extraembryonic fates.Retrovirology 03/2012; 9:21. · 6.47 Impact Factor -
Article: TM4SF1, a novel primary androgen receptor target gene over-expressed in human prostate cancer and involved in cell migration.
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ABSTRACT: The Androgen Receptor (AR) plays a key role in controlling prostate gland homeostasis and contributes to prostate carcinogenesis. The identification of its target genes should provide new candidates that may be implicated in cancer initiation and progression. Transcriptomic experiments and chromatin immunoprecipitation were combined to identify direct androgen regulated genes. Real-time quantitative PCR (RT-qPCR) analyses were performed to measure TM4SF1 mRNA levels in prostate cancer and benign prostatic hyperplasia (BPH) specimens. Immunohistochemical methods were used to compare TM4SF1 protein expression profiles in the same cohort. A targeted siRNAs knockdown strategy was used, prior to wound healing assays, to analyze the role of TM4SF1 in cell migration in vitro. We demonstrate for the first time that TM4SF1 is a direct target gene of the AR, a transcription factor of the steroid nuclear receptor family. A functional androgen response element was identified in the promoter region of the gene. In addition, TM4SF1 mRNA expression was higher in cancer samples compared to BPH tissues. The TM4SF1 protein mediates cell motility of prostate cancer cells where it is predominantly localized in the cytoplasm, in contrast to its apical membrane localization in normal prostate epithelial cells. Our results reveal a novel function for TM4SF1 in AR signaling. The TM4SF1 mRNA expression is higher in prostate cancer tissues as compared to BPH samples. Inhibition of cell migration after targeted knockdown of TM4SF1 protein expression suggests its contribution to prostate cancer cell metastasis.The Prostate 08/2011; 71(11):1239-50. · 3.48 Impact Factor -
Article: An electroneutral macrocyclic iron(II) complex that enhances MRI contrast in vivo.
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ABSTRACT: The first example of a macrocyclic ferrous complex, where two tetrazolyl pendent arms compensate the charge of the metal center, is synthesized and examined for its capacity to enhance MRI contrast in vitro and in vivo in the mouse.Journal of Medicinal Chemistry 06/2011; 54(12):4274-8. · 4.80 Impact Factor -
Article: The overexpression of the putative gut stem cell marker Musashi-1 induces tumorigenesis through Wnt and Notch activation.
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ABSTRACT: The RNA-binding protein Musashi-1 (Msi1) has been proposed as a marker of intestinal epithelial stem cells. These cells are responsible for the continuous renewal of the intestinal epithelium. Although the function of Msi1 has been studied in several organs from different species and in mammalian cell lines, its function and molecular regulation in mouse intestinal epithelium progenitor cells are still undefined. We describe here that, in these cells, the expression of Msi1 is regulated by the canonical Wnt pathway, through a mechanism involving a functional Tcf/Lef binding site on its promoter. An in vitro study in intestinal epithelium primary cultures showed that Msi1 overexpression promotes progenitor proliferation and activates Wnt and Notch pathways. Moreover, Msi1-overexpressing cells exhibit tumorigenic properties in xenograft experiments. These data point to a positive feedback loop between Msi1 and Wnt in intestinal epithelial progenitors. They also suggest that Msi1 has oncogenic properties in these cells, probably through induction of both the Wnt and Notch pathways.Journal of Cell Science 10/2010; 123(Pt 19):3256-65. · 6.11 Impact Factor
