The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.
Metabolomics is the newest "omics" science. It is a dynamic portrait of the metabolic status of living systems. Metabolomics has brought new insights on metabolic fluxes and a more comprehensive and holistic understanding of a cell's environment. This burgeoning field promises to be a potential tool to fill the gap between genotype and phenotype. As its preceding "omics" sciences (ie, genomics and proteomics), metabolomics' aim is to dredge information hidden in a sea of data. This technology permits simultaneous monitoring of many hundreds, or thousands, of macro- and small molecules, as well as functional monitoring of multiple pivotal cellular pathways. In addition, elucidation of cellular responses to molecular damage, including evolutionarily conserved inducible molecular defense systems, could be achieved with metabolomics and could lead to the discovery of new biomarkers of molecular responses to functional perturbations. If metabolomic information could be translated into diagnostic tests, it might have the potential to impact on clinical practice, and it might lead to the supplementation of traditional biomarkers of cellular integrity, cell and tissue homeostasis, and morphological alterations that result from cell damage or death. In this review the concept and characteristics of metabolomics are introduced. Main current applications of metabolomics in cancer research are reviewed, including its potential in the drug discovery field, and, last but not least, its potential impact in the field of monitoring response and toxicity to anticancer agents. In the last section, research projects ongoing at our institution and future challenges for metabolomics will be presented and briefly discussed.
Neuronal ELAV-like proteins (HuB, HuC, and HuD) are highly conserved RNA-binding proteins able to selectively associate with the 3 UTR of a subset of target mRNAs and increase their cytoplasmic stability and rate of translation. We previously demonstrated the involvement of these proteins in learning, reporting that they undergo a sustained up-regulation in the hippocampus of mice trained in a spatial discrimination task. Here, we extend this finding, showing that a similar up-regulation occurs in the hippocampus of rats trained in another spatial learning paradigm, the Morris water maze. HuD, a strictly neuron-specific ELAV-like protein, is shown to increase after learning, with a preferential binding to the cytoskeletal fraction. HuD up-regulation is associated with an enhancement of GAP-43 mRNA and protein levels, with an apparently increased HuD colocalization with the GAP-43 mRNA and an increased association of neuronal ELAV-like proteins with the GAP-43 mRNA. These learning-dependent biochemical events appear to be spatiotemporally controlled, because they do not occur in another brain region involved in learning, the retrosplenial cortex, and at the level of protein expression they show extinction 1 month after training despite memory retention. By contrast, HuD mRNA levels still remain increased after 1 month in the CA1 region. This persistence may have implications for long-term memory recall.
Neuronal cells strongly depend on the control exerted by RNA-binding proteins (RBPs) on gene expression for the establishment and maintenance of their phenotype. Neuronal ELAV (nELAV) proteins are RBPs able to influence virtually every aspect of the postsynthesis fate of bound mRNAs, from polyadenylation, alternative splicing and nuclear export to cytoplasmic localization, stability and translation. They enhance gene expression through the last two, best documented activities, increasing mRNA half-life and promoting protein synthesis by a still-unknown molecular mechanism. Developmentally, nELAV proteins have been shown to act as inducers of the transition between neural stem/progenitor cells and differentiation-committed cells, also assisting these neuroblasts in the completion of their maturation program. In brain physiology, they are also the first RBPs demonstrated to have a pivotal role in memory, where they probably control mRNA availability for translation in subcellular domains, thereby providing a biochemical means for selective increase in synaptic strength.
Long-lasting changes in cellular functions require reprogramming of protein synthesis as a result of cell signaling events that influence nuclear transcription and͞or the fate of the transcribed mRNAs, ultimately leading to changed mRNA availability to the ribosome. Posttranscriptional mechanisms are emerging as key controllers of gene expression (reviewed in refs. 1 and 2) and are postulated to be critical for the localized changes in protein levels involved in cell differentiation and in the maintenance of the differentiated phenotype, especially in polarized cells such as neurons (3). Modulation of mRNA decay appears to be an efficient posttranscriptional way of controlling expression, because small changes in mRNA half-life can radically alter the abundance of a given mRNA and the amount of the relevant protein (4). Indeed, the decay rates of many mRNAs are governed by defined sequence determinants and by RNA-binding proteins (RBPs) acting on these determinants. The best-characterized regulative cis motifs in mammalian mRNAs are the AREs (adenine-and uridine-rich elements), which are found in the 3Ј UTRs of mRNAs endowed with a rapid response to cell environmental stimuli, as in many cytokines and oncogenes (reviewed in ref. 5).In the human genome, a general ARE consensus is present in 5-8% of expressed genes (6), and it represents a docking site for RBPs controlling mRNA stability, probably by modulation of exosome activity (7). ARE-dependent mRNA decay has been shown to be a target of at least two signaling cascades. The first is the p38 mitogen-activated protein kinase (MAPK)-MAPKAPK2 pathway, which, when activated, stabilizes ARE-bearing interleukin mRNAs (8-10), possibly through inactivation of the ARE-binding, mRNA-destabilizing RBP tristetraprolin (11, 12). The second pathway, which has been less investigated, is triggered by phorbol esters (phorbol 12-myristate 13-acetate, PMA) and calcium ionophore administration to culture cells, leading again to stabilization of ARE-bearing mRNAs (13-19). For its features, this pathway could involve the calcium-and diacylglycerol-regulated PKC isozymes, possibly resulting in the activation of a downstream function able to induce stabilization of ARE-bearing mRNAs. Fifteen years ago, Malter and coworkers (20, 21) identified a factor of Ϸ32 kDa, which they called AUBF for AU-rich binding factor, that was induced to bind ARE sequences after brief PMA treatment or calcium influx and was inactivated by dephosphorylation in peripheral blood mononuclear cells. AUBF was shown to be almost entirely located on polysomes when stimulated (22).ELAV (embryonic lethal abnormal vision) proteins, or Hu antigens, represent the best-studied ARE-binding RBPs and are known from a substantial body of evidence to stabilize target mRNAs in the cytoplasm (reviewed in refs. 23 and 24). In vertebrates, HuB, HuC, and HuD are neuron-specific members of the ELAV family (nELAV proteins), whereas HuR is ubiquitously expressed; all four proteins are highly homologous in sequence, are Ϸ40 kDa in s...
The view that memory is encoded by variations in the strength of synapses implies that long-term biochemical changes take place within subcellular microdomains of neurons. These changes are thought ultimately to be an effect of transcriptional regulation of specific genes. Localized changes, however, cannot be fully explained by a purely transcriptional control of gene expression. The neuron-specific ELAV-like HuB, HuC, and HuD RNA-binding proteins act posttranscriptionally by binding to adenine-and uridinerich elements (AREs) in the 3 untranslated region of a set of target mRNAs, and by increasing mRNA cytoplasmic stability and͞or rate of translation. Here we show that neuronal ELAV-like genes undergo a sustained up-regulation in hippocampal pyramidal cells only of mice and rats that have learned a spatial discrimination paradigm. This learning-specific increase of ELAV-like proteins was localized within cytoplasmic compartments of the somata and proximal dendrites and was associated with the cytoskeleton. This increase was also accompanied by enhanced expression of the GAP-43 gene, known to be regulated mainly posttranscriptionally and whose mRNA is demonstrated here to be an in vivo ELAV-like target. Antisense-mediated knockdown of HuC impaired spatial learning performance in mice and induced a concomitant downregulation of GAP-43 expression. Neuronal ELAV-like proteins could exert learning-induced posttranscriptional control of an array of target genes uniquely suited to subserve substrates of memory storage.
Insulin regulates glycaemia, lipogenesis and increases mRNA translation. Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin. The role of insulin-regulated translation is unknown. Here we show that reduction of insulin-regulated translation in mice heterozygous for eIF6 results in normal glycaemia, but less blood cholesterol and triglycerides. eIF6 controls fatty acid synthesis and glycolysis in a cell autonomous fashion. eIF6 acts by exerting translational control of adipogenic transcription factors like C/EBPβ, C/EBPδ and ATF4 that have G/C rich or uORF sequences in their 5′ UTR. The outcome of the translational activation by eIF6 is a reshaping of gene expression with increased levels of lipogenic and glycolytic enzymes. Finally, eIF6 levels modulate histone acetylation and amounts of rate-limiting fatty acid synthase (Fasn) mRNA. Since obesity, type 2 diabetes, and cancer require a Fasn-driven lipogenic state, we propose that eIF6 could be a therapeutic target for these diseases.
Tumour onset and progression are due to the accumulation of genomic lesions, which alter gene expression and ultimately proteome activities. These lesions are thought to affect primarily the transcriptional control of gene expression. In the present study, we aimed at evaluating the genome-wide occurrence of alterations in the translational control exploiting an isogenic, phenotypically validated cellular model of colorectal cancer (CRC) transition from invasive carcinoma to metastasis. In this model, microarray profiling shows that changes in the level of messenger ribonucleic acid (mRNA) association with polysomes occur more than 2-fold than changes in the level of total cellular mRNA. When common to both the total and polysomal compartments, these changes are also homodirectional, being amplified in magnitude at the polysomal level. Comparison between the transcriptional and the translational fluctuations revealed distinct signatures of statistically over-represented gene functions, involving the program of cell proliferation for both levels of analysis, while the apoptosis and the translation programs were affected mainly at translation. Looking for an upstream determinant of translational deregulation, we found an increase in the hyperphosphorylated form of the 4E-BP1 protein in the metastatic cell line, possibly resulting in an increased activation of cap-dependent translation due to increased activity of the eIF4E protein. Analysis of the distribution profiles for the 5' untranslated region (5'-UTR) length of the changed genes showed an association between longer 5'-UTRs and the probability for the relevant gene to be altered translationally, consistent with enhanced eIF4E function. This genome-wide analysis is in favour of a model of profound alteration of translational control in late CRC progression. It also suggests polysomal mRNA profiles as a new, informative dimension for the study of transcriptome imbalance in cancer.
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