Publications (41) View all
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Article: Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program.
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ABSTRACT: S6 kinases (S6Ks) are mechanistic target of rapamycin substrates that participate in cell growth control. S6Ks phosphorylate ribosomal protein S6 (rpS6) and additional proteins involved in the translational machinery, although the functional roles of these modifications remain elusive. Here we analyze the S6K-dependent transcriptional and translational regulation of gene expression by comparing whole-genome microarray of total and polysomal mouse liver RNA after feeding. We show that tissue lacking S6Ks 1 and 2 (S6K1 and S6K2), displays a defect in the ribosome biogenesis (RiBi) transcriptional program after feeding. Over 75% of RiBi factors are controlled by S6K, including Nop56, Nop14, Gar1, Rrp9, Rrp15, Rrp12 and Pwp2 nucleolar proteins. Importantly, the reduced activity of RiBi transcriptional promoters in S6K1;S6K2(-/-) cells is also observed in rpS6 knock-in mutants that cannot be phosphorylated. As ribosomal protein synthesis is not affected by these mutations, our data reveal a distinct and specific aspect of RiBi under the control of rpS6 kinase activity, that is, the RiBi transcriptional program.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.606.Oncogene 01/2013; · 6.37 Impact Factor -
Article: FADD protein release mirrors the development and aggressiveness of human non-small cell lung cancer.
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ABSTRACT: The need to unfold the underlying mechanisms of lung cancer aggressiveness, the deadliest cancer in the world, is of prime importance. Because Fas-associated death domain protein (FADD) is the key adaptor molecule transmitting the apoptotic signal delivered by death receptors, we studied the presence and correlation of intra- and extracellular FADD protein with development and aggressiveness of non-small cell lung cancer (NSCLC). Fifty NSCLC patients were enrolled in this prospective study. Intracellular FADD was detected in patients' tissue by immunohistochemistry. Tumours and distant non-tumoural lung biopsies were cultured through trans-well membrane in order to analyse extracellular FADD. Correlation between different clinical/histological parameters with level/localisation of FADD protein has been investigated. Fas-associated death domain protein could be specifically downregulated in tumoural cells and FADD loss correlated with the presence of extracellular FADD. Indeed, human NSCLC released FADD protein, and tumoural samples released significantly more FADD than non-tumoural (NT) tissue (P=0.000003). The release of FADD by both tumoural and NT tissue increased significantly with the cancer stage, and was correlated with both early and late steps of the metastasis process. The release of FADD by human NSCLC could be a new marker of poor prognosis as it correlates positively with both tumour progression and aggressiveness.British Journal of Cancer 06/2012; 106(12):1989-96. · 5.04 Impact Factor -
Article: Lung tumor microenvironment induces specific gene expression signature in intratumoral NK cells.
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ABSTRACT: Natural killer (NK) cells are able to recognize and kill tumor cells, however whether they contribute to tumor immunosurveillance is still debated. Our previous studies demonstrated the presence of NK cells in human lung tumors. Their comparison with NK cells from non-tumoral lung tissues and with blood NK cells from the same individuals revealed a decreased expression of some NK receptors and impaired ex vivo cytotoxic functions occurring specifically in NK cells isolated from the tumor microenvironment. The aim of the present study was to characterize the transcriptional profile of such intratumoral NK cells, by comparative microarray analysis of sorted NK cells isolated from non-tumoral (Non-Tum-NK) and tumoral (Tum-NK) lung tissues of 12 Non-Small Cell Lung Cancer patients. Our results reveal a specific gene expression signature of Tum-NK cells particularly in activation processes and cytotoxicity, confirming that tumor environment induces modifications in NK cells biology. Indeed, intratumoral NK cells display higher expression levels of NKp44, NKG2A, Granzymes A and K, and Fas mRNA. A particular pattern of receptors involved in chemotaxis was also observed, with an overexpression of CXCR5 and CXCR6, and a lower expression of CX3CR1 and S1PR1 genes in Tum-NK as compared to Non-Tum-NK cells. The precise identification of the molecular pathways modulated in the tumor environment will help to decipher the role of NK cells in tumor immunosurveillance and will open future investigations to manipulate their antitumoral functions.Frontiers in immunology. 01/2013; 4:19. -
Article: Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes.
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ABSTRACT: More than 90% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene that encodes the methyl-CpG-binding protein 2, a transcriptional modulator. Because MECP2 is subjected to X chromosome inactivation (XCI), girls with RTT either express the wild-type or mutant allele in each individual cell. To test the consequences of MECP2 mutations resulting from a genome-wide transcriptional dysregulation and to identify its target genes in a system that circumvents the functional mosaicism resulting from XCI, we carried out gene expression profiling of clonal populations derived from fibroblast primary cultures expressing exclusively either the wild-type or the mutant MECP2 allele. Clonal cultures were obtained from skin biopsy of three RTT patients carrying either a non-sense or a frameshift MECP2 mutation. For each patient, gene expression profiles of wild-type and mutant clones were compared by oligonucleotide expression microarray analysis. Firstly, clustering analysis classified the RTT patients according to their genetic background and MECP2 mutation. Secondly, expression profiling by microarray analysis and quantitative RT-PCR indicated four up-regulated genes and five down-regulated genes significantly dysregulated in all our statistical analysis, including excellent potential candidate genes for the understanding of the pathophysiology of this neurodevelopmental disease. Thirdly, chromatin immunoprecipitation analysis confirmed MeCP2 binding to respective CpG islands in three out of four up-regulated candidate genes and sequencing of bisulphite-converted DNA indicated that MeCP2 preferentially binds to methylated-DNA sequences. Most importantly, the finding that at least two of these genes (BMCC1 and RNF182) were shown to be involved in cell survival and/or apoptosis may suggest that impaired MeCP2 function could alter the survival of neurons thus compromising brain function without inducing cell death.Journal of Cellular and Molecular Medicine 07/2010; 14(7):1962-74. · 4.13 Impact Factor -
Article: GExMap: An Intuitive Visual Tool to Detect and Analyze Genomic Distribution in Microarray-generated Lists of Differentially Expressed Genes
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ABSTRACT: BackgroundHigh- throughput technologies, as DNA microarrays, generate a huge amount of data, which are difficult to interpret. Biologists require easy-to-use tools to analyze them and explore new scientific hypotheses. We propose a visual data mining tool to extract a new type of useful genomic information buried in gene lists generated bydifferential expression studies. We compare the genomic distribution that is observed within the gene list with the expected distribution, which is estimated from public genomic databases. An algorithm of research and a statistical test give reliable and optimal results. GExMap helps identify genomic regions that are enriched in genes whose differential expression is of potential interest for target diseases. This software is freely available20and easily customized. Since sources are frequently updated, it offers tools for updates at any moment. GExMap is usable by any commercially and publicly available microarray platform. Furthermore, GExMap helps in interpretation by showing an ordered list for each gene ontology. Presently, GExMap can also be used to analyse gene lists not only from the Homo sapiens genome but also the Mus musculus and the Rattus norvegicus genomes.ResultsGExMap is designed to be an easy-to-use software with visual and intuitive interpretation of results. We have chosen to develop the software with R1 language to allow total compatibility with every operating system. ENSEMBL2 was chosen as a reference identifier for genes, meaning that GExMap requires a pre-processing step to match and replace most of the common user’s identifier types (Unigene, Affymetrix, Agilent, etc) by ENSEMBL identifiers. The choice of a reference genome for this pre-processing step allows compatibility with several databases and microarray identifiers. In the same step, GExMap creates a new table with all ENSEMBL available information. GExMap is an open source project. Furthermore, its source structure and simple annotation facilitate customization.ConclusionsBiological interpretation of bioinformatics data is an ongoing and challenging task. Scientists need to access to types of information buried in biological databases. From microarray data, GExMap indicates the observed genomic distribution of the regulated genes and statistically compares it to the expected genomic distribution. Statistical analysis of relative genomic distribution is a potentially powerful and informative approach to microarray datainterpretation. GExMap provides biologists with easy access to this new type of information.Journal of Proteomics & Bioinformatics. 01/2009;
