Annuaire
2011
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A conceptually improved TD-DFT approach for predicting the maximum absorption wavelength of cyanine dyes
- Journal : Dyes and Pigments
- 2011
- Cyanine dyes have found valuable applications in modern bioresearch because of their biocompatibility, high molar absorptivity and moderate fluorescence quantum yield. Of special value for sensing and labeling applications is the fact they can cover a very large spectral range (from blue to infra-red). To design and select the most appropriate dyes for a given application the computational prediction of the absorption wavelength (prior to the costly chemical synthesis) serves as a valuable guidance. However, predicting absorption and emission wavelengths of such compounds remains a challenging task. Herein, we report a fast and highly accurate computational approach which allows the prediction of the maximum absorption wavelength for a wide range of cyanine dyes, including symmetrical and unsymmetrical, trimethine and pentamethine cyanine dyes but also unusual imino-based analogues. In addition to the vertical excitation energy (calculated from time-dependent density functional theory), the approach makes use of a novel correction term that is based on the ground-state zero-point vibrational energy (ZPVE). The correction term is statistically significant (F-test), and it reduces the average error and maximal error of the prediction by a factor of two. We anticipate that the concept of including the ZPVE into the calculation of the maximum absorption wavelength can be used also for other families of dyes to improve their predictability.
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A conserved splicing mechanism of the LMNA gene controls premature aging
- Journal : Hum Mol Genet
- 2011
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A conserved splicing mechanism of the LMNA gene controls premature aging.
- Journal : Hum Mol Genet
- 2011
- Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases of HGPS are due to a heterozygous silent mutation (c.1824C>T; p.Gly608Gly) that enhances the use of an internal 5' splice site (5'SS) in exon 11 of the LMNA pre-mRNA and leads to the production of a truncated protein (progerin) with a dominant negative effect. Here we show that HGPS mutation changes the accessibility of the 5'SS of LMNA exon 11 which is sequestered in a conserved RNA structure. Our results also reveal a regulatory role of a subset of serine-arginine (SR)-rich proteins, including serine-arginine rich splicing factor 1 (SRSF1) and SRSF6, on utilization of the 5'SS leading to lamin A or progerin production and a modulation of this regulation in the presence of the c.1824C>T mutation is shown directly on HGPS patient cells. Mutant mice carryingthe equivalent mutation in the LMNA gene (c.1827C>T) also accumulate progerin and phenocopy the main cellular alterations and clinical defects of HGPS patients. RNAi-induced depletion of SRSF1 in the HGPS-like mouse embryonic fibroblasts (MEFs) allowed progerin reduction and dysmorphic nuclei phenotype correction, whereas SRSF6 depletion aggravated the HGPS-like MEF's phenotype. We demonstratethat changes in the splicing ratio between lamin A and progerin are key factors for lifespan since heterozygous mice harboring the mutation lived longer than homozygous littermates but less than the wild-type. Genetic and biochemical datatogether favor the view that physiological progerin production is under tight control of a conserved splicing mechanism to avoid precocious aging.
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Activation of a microRNA response in trans reveals a new role for poly(A) in translational repression.
- Journal : Nucleic Acids Res
- 2011
- Here, we report that the untreated rabbit reticulocyte lysate contains over 300 different endogenous microRNAs together with the major components of the RNA-induced silencing complex and thus can be used as a model in vitro system tostudy the effects of microRNAs on gene expression. By using this system, we wereable to show that microRNA hybridization to its target resulted in a very rapid and strong inhibition of expression that was exerted exclusively at the level oftranslation initiation with no involvement of transcript degradation or deadenylation. Moreover, we demonstrate that the magnitude of microRNA-induced repression can only be recapitulated in the context of a competitive translatingenvironment. By using a wide spectrum of competitor cellular and viral RNAs, we could further show that competition was not exerted at the level of general components of the translational machinery, but relied exclusively on the presence of the poly(A) tail with virtually no involvement of the cap structure.
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Biological functions of p53 isoforms through evolution: lessons from animal and cellular models.
- Journal : Cell Death Differ
- 2011
- The TP53 tumour-suppressor gene is expressed as several protein isoforms generated by different mechanisms, including use of alternative promoters, splicing sites and translational initiation sites, that are conserved through evolution and within the TP53 homologues, TP63 and TP73. Although first described in the eighties, the importance of p53 isoforms in regulating the suppressive functions of p53 has only become evident in the last 10 years, by analogy with observations that p63 and p73 isoforms appeared indispensable to fully understand the biological functions of TP63 and TP73. This review summarizes recent advances in the field of 'p53 isoforms', including new data on p63 and p73 isoforms. Details of the alternative mechanisms that produce p53 isoforms and cis- and trans-regulators identified are provided. The main focus is on their biological functions (apoptosis, cell cycle, aging and so on) in cellular and animal models, including mouse, zebrafish and Drosophila. Finally, the deregulation of p53 isoform expression in human cancers is reviewed. Based on these latest results, several developments are expected in the future: the identification of drugs modulating p53 isoform expression; the generation of animal models and the evaluation of the use of p53 isoform as biomarkers in human cancers.
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Caenorhabditis elegans chromatin-associated proteins SET-2 and ASH-2 are differentially required for histone H3 Lys 4 methylation in embryos and adult germ cells.
- Journal : Proc Natl Acad Sci U S A
- 2011
- Methylation of histone H3 lysine 4 (H3K4me), a mark associated with gene activation, is mediated by SET1 and the related mixed lineage leukemia (MLL) histone methyltransferases (HMTs) across species. Mammals contain seven H3K4 HMTs, Set1A, Set1B, and MLL1-MLL5. The activity of SET1 and MLL proteins relies on protein-protein interactions within large multisubunit complexes that includethree core components: RbBP5, Ash2L, and WDR5. It remains unclear how the composition and specificity of these complexes varies between cell types and during development. Caenorhabditis elegans contains one SET1 protein, SET-2, oneMLL-like protein, SET-16, and single homologs of RbBP5, Ash2L, and WDR5. Here weshow that SET-2 is responsible for the majority of bulk H3K4 methylation at all developmental stages. However, SET-2 and absent, small, or homeotic discs 2 (ASH-2) are differentially required for tri- and dimethylation of H3K4 (H3K4me3 and -me2) in embryos and adult germ cells. In embryos, whereas efficient H3K4me3requires both SET-2 and ASH-2, H3K4me2 relies mostly on ASH-2. In adult germ cells by contrast, SET-2 serves a major role whereas ASH-2 is dispensable for H3K4me3 and most H3K4me2. Loss of SET-2 results in progressive sterility over several generations, suggesting an important function in the maintenance of a functional germ line. This study demonstrates that individual subunits of SET1-related complexes can show tissue specificity and developmental regulation and establishes C. elegans as a model to study SET1-related complexes in a multicellular organism.
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Caenorhabditis elegans Heterochromatin protein 1 (HPL-2) links developmental plasticity, longevity and lipid metabolism.
- Journal : Genome Biol
- 2011
- BACKGROUND: Heterochromatin protein 1 (HP1) family proteins have a well-characterized role in heterochromatin packaging and gene regulation. Their function in organismal development, however, is less well understood. Here we used genome-wide expression profiling to assess novel functions of the Caenorhabditis elegans HP1 homolog HPL-2 at specific developmental stages. RESULTS: We show that HPL-2 regulates the expression of germline genes, extracellular matrix components and genes involved in lipid metabolism. Comparison of our expression data with HPL-2 ChIP-on-chip profiles reveals that a significant number of genes up- and down-regulated in the absence of HPL-2 are bound by HPL-2. Germline genes are specifically up-regulated in hpl-2 mutants, consistent with the function of HPL-2 as a repressor of ectopic germ cell fate. In addition, microarray results and phenotypic analysis suggest that HPL-2 regulates the dauer developmental decision, a striking example of phenotypic plasticity in which environmental conditions determine developmental fate. HPL-2acts in dauer at least partly through modulation of daf-2/IIS and TGF-beta signaling pathways, major determinants of the dauer program. hpl-2 mutants also show increased longevity and altered lipid metabolism, hallmarks of the long-lived, stress resistant dauers. CONCLUSIONS: Our results suggest that the worm HP1 homologue HPL-2 may coordinately regulate dauer diapause, longevity andlipid metabolism, three processes dependent on developmental input and environmental conditions. Our findings are of general interest as a paradigm of how chromatin factors can both stabilize development by buffering environmental variation, and guide the organism through remodeling events that require plasticity of cell fate regulation.
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Cholesterol synthesis-related enzyme oxidosqualene cyclase is required to maintain self-renewal in primary erythroid progenitors.
- Journal : Cell Prolif
- 2011
- OBJECTIVES: Molecular mechanisms controlling cell fate decision making in self-renewing cells are poorly understood. A previous transcriptomic study, carried out in primary avian erythroid progenitor cells (T2ECs), revealed that the gene encoding oxidosqualene cyclase (OSC/LSS), an enzyme involved in cholesterol biosynthesis, is significantly up-regulated in self-renewing cells. The aim of the present work is to understand whether this up-regulation is required for self-renewal maintenance and what are the mechanisms involved. MATERIALS AND METHODS: To investigate OSC function, we studied effects of its enzymatic activity inhibition using Ro48-8071, a specific OSC inhibitor. In addition, we completed this pharmacological approach by RNAi-mediated OSC/LSS knockdown. The study of OSC inhibition was carried out on both self-renewing anddifferentiating cells to observe any state-dependent effect. RESULTS: Our data show that OSC acts both by protecting self-renewing T2EC cells from apoptosis and by blocking their differentiation program, as OSC inhibition is sufficient to trigger spontaneous commitment of self-renewing cells towards an early differentiation state. This is self-renewal specific, as OSC inhibition has no effect on erythroid progenitors that have already differentiated. CONCLUSIONS: Taken together, our results suggest that OSC/LSS expression and activity are required to maintain cell self-renewal and may be involved in the self-renewal versus differentiation/apoptosis decision making, by keeping cells in a self-renewal state.
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Differential evolvability along lines of least resistance of upper and lower molars in island house mice.
- Journal : PLoS One
- 2011
- Variation within a population is a key feature in evolution, because it can increase or impede response to selection, depending on whether or not the intrapopulational variance is correlated to the change under selection. Hence, main directions of genetic variance have been proposed to constitute "lines of least resistance to evolution" along which evolution would be facilitated. Yet, the screening of selection occurs at the phenotypic level, and the phenotypic variance is not only the product of the underlying genetic variance, but also ofdevelopmental processes. It is thus a key issue for interpreting short and long term evolutionary patterns to identify whether main directions of phenotypic variance indeed constitute direction of facilitated evolution, and whether this is favored by developmental processes preferably generating certain phenotypes. We tackled these questions by a morphometric quantification of the directions ofvariance, compared to the direction of evolution of the first upper and lower molars of wild continental and insular house mice. The main phenotypic variance indeed appeared as channeling evolution between populations. The upper molar emerged as highly evolvable, because a strong allometric component contributed to its variance. This allometric relationship drove a repeated but independent evolution of a peculiar upper molar shape whenever size increased. This repeatedevolution, together with knowledge about the molar development, suggest that themain direction of phenotypic variance correspond here to a "line of least developmental resistance" along which evolution between population is channeled.
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Epigenetic maintenance of telomere identity in Drosophila: buckle up for the sperm ride.
- Journal : Cell Cycle
- 2011
- A critical function of telomeres is to prevent the ligation of chromosome ends by DNA repair enzymes. In most eukaryotes, telomeric DNA consists in large arrays of G-rich tandem repeats that are recognized by DNA binding capping proteins. Drosophila telomeres are unusual as they lack short tandem repeats. However, Drosophila capping proteins can bind chromosome extremities in a DNA sequence-independent manner. This epigenetic protection of fly telomeres has been essentially studied in somatic cells where capping proteins such as HOAP or HP1 are essential in preventing chromosome end-to-end fusions. HipHop and K81 are two recently identified paralogous capping proteins with complementary expression patterns. While HipHop is involved in telomere capping in somatic cells, K81 hasspecialized in the protection of telomeres in post-meiotic male germ cells. Remarkably, K81 is required for the stabilization of HOAP and HP1 at telomeres during the massive paternal chromatin remodeling that occurs during spermiogenesis and at fertilization. We thus propose that the maintenance of capping proteins at Drosophila sperm telomeres is crucial for the transmission of telomere identity to the diploid zygote. :
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Epigenetics in C. elegans: facts and challenges.
- Journal : Genesis
- 2011
- Epigenetics is defined as the study of heritable changes in gene expression thatare not accompanied by changes in the DNA sequence. Epigenetic mechanisms include histone post-translational modifications, histone variant incorporation, non-coding RNAs, and nucleosome remodeling and exchange. In addition, the functional compartmentalization of the nucleus also contributes to epigenetic regulation of gene expression. Studies on the molecular mechanisms underlying epigenetic phenomena and their biological function have relied on various model systems, including yeast, plants, flies, and cultured mammalian cells. Here we will expose the reader to the current understanding of epigenetic regulation in the roundworm C. elegans. We will review recent models of nuclear organization and its impact on gene expression, the biological role of enzymes modifying corehistones, and the function of chromatin-associated factors, with special emphasis on Polycomb (PcG) and Trithorax (Trx-G) group proteins. We will discuss how the C. elegans model has provided novel insight into mechanisms of epigenetic regulation as well as suggest directions for future research.
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Finding modulators of stochasticity levels by quantitative genetics.
- Journal : Methods Mol Biol
- 2011
- Although bakers and wine makers constantly select, compare, and hunt for new wild strains of Saccharomyces cerevisiae, yeast geneticists have long focused on a few "standard" strains to ensure reproducibility and easiness of experimentation. And so far, the wonderful natural resource of wild genetic variation has been poorlyexploited in most academic laboratories. We describe here how one can use this resource to investigate the molecular sources of stochasticity in a gene regulatory network. The approach is general enough to be applied to any network of interest, as long as the experimental read-out offers robust statistics. For a given network, a typical study first identifies two backgrounds A and B displaying different levels of stochasticity and then study the network in A x Bprogeny. Taking advantage of microarrays or resequencing technologies, genotyping of appropriate segregants can then lead to the genomic regions housing modulators of stochasticity. The powerful toolbox available to manipulate the yeast genome offers several ways to narrow these regions further and to unambiguously demonstrate the regulatory consequences of DNA polymorphisms.
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G-quadruplex-induced instability during leading-strand replication
- Journal : The EMBO journal
- 2011
- G‐quadruplexes are four‐stranded nucleic acid structures whose biological functions remain poorly understood. In the yeast S. cerevisiae, we report that G‐quadruplexes form and, if not properly processed, pose a specific challenge to replication. We show that the G‐quadruplex‐prone CEB1 tandem array is tolerated when inserted near ARS305 replication origin in wild‐type cells but is very frequently destabilized upon treatment with the potent Phen‐DC3 G‐quadruplex ligand, or in the absence of the G‐quadruplex‐unwinding Pif1 helicase, only when the G‐rich strand is the template of leading‐strand replication. The orientation‐dependent instability is associated with the formation of Rad51–Rad52‐dependent X‐shaped intermediates during replication detected by two‐dimensional (2D) gels, and relies on the presence of intact G‐quadruplex motifs in CEB1 and on the activity of ARS305. The asymmetrical behaviour of G‐quadruplex prone sequences during replication has implications for their evolutionary dynamics within genomes, including the maintenance of G‐rich telomeres.
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Genome-wide in silico identification of new conserved and functional retinoic acid receptor response elements (direct repeats separated by 5 bp).
- Journal : J Biol Chem
- 2011
- The nuclear retinoic acid receptors interact with specific retinoic acid (RA) response elements (RAREs) located in the promoters of target genes to orchestrate transcriptional networks involved in cell growth and differentiation. Here we describe a genome-wide in silico analysis of consensus DR5 RAREs based on the recurrent RGKTSA motifs. More than 15,000 DR5 RAREs were identified and analyzedfor their localization and conservation in vertebrates. We selected 138 elementslocated +/-10 kb from transcription start sites and gene ends and conserved across more than 6 species. We also validated the functionality of these RAREs by analyzing their ability to bind retinoic acid receptors (ChIP sequencing experiments) as well as the RA regulation of the corresponding genes (RNA sequencing and quantitative real time PCR experiments). Such a strategy provideda global set of high confidence RAREs expanding the known experimentally validated RAREs repertoire associated to a series of new genes involved in cell signaling, development, and tumor suppression. Finally, the present work provides a valuable knowledge base for the analysis of a wider range of RA-target genes in different species.
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Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2β in development
- Journal : PLoS Genet
- 2011
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Identification of evolutionarily conserved exons as regulated targets for the splicing activator tra2beta in development.
- Journal : PLoS Genet
- 2011
- Alternative splicing amplifies the information content of the genome, creating multiple mRNA isoforms from single genes. The evolutionarily conserved splicing activator Tra2beta (Sfrs10) is essential for mouse embryogenesis and implicated in spermatogenesis. Here we find that Tra2beta is up-regulated as the mitotic stem cell containing population of male germ cells differentiate into meiotic and post-meiotic cells. Using CLIP coupled to deep sequencing, we found that Tra2beta binds a high frequency of exons and identified specific G/A rich motifs as frequent targets. Significantly, for the first time we have analysed the splicing effect of Sfrs10 depletion in vivo by generating a conditional neuronal-specificSfrs10 knock-out mouse (Sfrs10(fl/fl); Nestin-Cre(tg/+)). This mouse has defectsin brain development and allowed correlation of genuine physiologically Tra2betaregulated exons. These belonged to a novel class which were longer than average size and importantly needed multiple cooperative Tra2beta binding sites for efficient splicing activation, thus explaining the observed splicing defects in the knockout mice. Regulated exons included a cassette exon which produces a meiotic isoform of the Nasp histone chaperone that helps monitor DNA double-strand breaks. We also found a previously uncharacterised poison exon identifying a new pathway of feedback control between vertebrate Tra2 proteins. Both Nasp-T and the Tra2a poison exon are evolutionarily conserved, suggesting they might control fundamental developmental processes. Tra2beta protein isoforms lacking the RRM were able to activate specific target exons indicating an additional functional role as a splicing co-activator. Significantly the N-terminal RS1 domain conserved between flies and humans was essential for the splicing activator function of Tra2beta. Versions of Tra2beta lacking this N-terminal RS1 domain potently repressed the same target exons activated by full-length Tra2beta protein.
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Identification of human, rat and chicken ribosomal proteins by a combination of two-dimensional polyacrylamide gel electrophoresis and mass spectrometry.
- Journal : J Proteomics
- 2011
- To identify the exact spot position of human, rat and chicken ribosomal proteins(RP) separated by two-dimensional polyacrylamide gel electrophoresis (2-DE), a 2-DE system was designed to separate RP with a pI>8.6 according to their charge in the first dimension and to their molecular mass in the second dimension. Individual proteins were excised from the gels and identified by mass spectrometry after digestion by trypsin. In addition, a mixture of purified RP from these three species was also analyzed by tandem mass tag spectrometry. By combining those two methods 74 RP from human, 76 from rat and 67 from chicken were identified according to the nomenclature initially defined for rat liver RPand by using the Swiss-Prot/trEMBL databases. Whereas human and rat RP were welldescribed, most of RP from chicken were not characterized in databases, since 35out of 67 chicken RP identified in this study were not listed yet. We propose here the first comprehensive description of chicken RP and their comparison to those from human and rat.
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Integrated genome-scale prediction of detrimental mutations in transcription networks.
- Journal : PLoS Genet
- 2011
- A central challenge in genetics is to understand when and why mutations alter the phenotype of an organism. The consequences of gene inhibition have been systematically studied and can be predicted reasonably well across a genome. However, many sequence variants important for disease and evolution may alter gene regulation rather than gene function. The consequences of altering a regulatory interaction (or "edge") rather than a gene (or "node") in a network have not been as extensively studied. Here we use an integrative analysis and evolutionary conservation to identify features that predict when the loss of a regulatory interaction is detrimental in the extensively mapped transcription network of budding yeast. Properties such as the strength of an interaction, location and context in a promoter, regulator and target gene importance, and the potential for compensation (redundancy) associate to some extent with interaction importance. Combined, however, these features predict quite well whether the loss of a regulatory interaction is detrimental across many promoters and for many different transcription factors. Thus, despite the potential for regulatory diversity, common principles can be used to understand and predict when changes in regulation are most harmful to an organism.
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microRNA complements in deuterostomes: origin and evolution of microRNAs.
- Journal : Evol Dev
- 2011
- Although numerous studies have emphasized the role of microRNAs (miRNAs) in the control of many different cellular processes, they might also exert a profound effect on the macroevolution of animal body plans. It has been hypothesized that, because miRNAs increase genic precision and are continuously being added to metazoan genomes through geologic time, miRNAs might be instrumental for canalization of development and morphological evolution. Nonetheless, an outstanding question remains: how are new miRNAs constantly evolving? To addressthis question, we assessed the miRNA complements of four deuterostome species, chosen because of their sequenced genomes and well-resolved phylogeny. Our comparative analysis shows that each of these four species is characterized by aunique repertoire of miRNAs, with few instances of miRNA loss. Moreover, we findthat almost half of the miRNAs identified in this study are located in intronic regions of protein coding genes, suggesting that new miRNAs might arise from intronic regions in a process we term intronic exaptation. We also show that miRNAs often occur within cotranscribed clusters, and describe the biological function of one of these conserved clusters, the miR-1/miR-133 cluster. Taken together, our work shows that miRNAs can easily emerge within already transcribed regions of DNA, whether it be introns or preexisting clusters of miRNAs and/or miRNAs and protein coding genes, and because of their regulatory roles, these novel players change the structure of gene regulatory networks, with potential macroevolutionary results.
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Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy
- Journal : Nat Med
- 2011
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Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy
- Journal : Nat Struct Mol Biol
- 2011
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Molecular design of a splicing switch responsive to the RNA binding protein Tra2beta.
- Journal : Nucleic Acids Res
- 2011
- Tra2beta regulates a number of splicing switches including activation of the human testis-specific exon HIPK3-T in the Homeodomain Interacting Protein Kinase3 gene. By testing HIPK3-T exons of different intrinsic strengths, we found Tra2beta most efficiently activated splicing inclusion of intrinsically weak exons, although these were spliced at a lower overall level. Both the RRM and N-terminal RS-rich region of Tra2beta were required for splicing activation. Bioinformatic searches for splicing enhancers and repressors mapped four physically distinct exonic splicing enhancers (ESEs) within HIPK3-T, each containing the known Tra2beta AGAA-rich binding site. Surprisingly disruption ofeach single ESE prevented Tra2beta-mediated activation, although single mutated exons could still bind Tra2beta protein by gel shifts and functional splicing analyses. Titration experiments indicate an additive model of HIPK3-T splicing activation, requiring availability of an array of four distinct ESEs to enable splicing activation. To enable this efficient Tra2beta-mediated splicing switch to operate, a closely adjacent downstream and potentially competitive stronger 5'-splice site is actively repressed. Our data indicate that a novel arrangementof multiple mono-specific AGAA-rich ESEs coupled to a weak 5'-splice site functions as a responsive gauge. This gauge monitors changes in the specific nuclear concentration of the RNA binding protein Tra2beta, and co-ordinately regulates HIPK3-T exon splicing inclusion.
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Molecular design of a splicing switch responsive to the RNA binding protein Tra2β
- Journal : Nucleic Acids Res
- 2011
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Novel genes differentially expressed between posterior and median silk gland identified by SAGE-aided transcriptome analysis.
- Journal : Insect Biochem Mol Biol
- 2011
- Serial analysis of gene expression (SAGE) profiles, from posterior and median cells of the silk gland of Bombyx mori, were analyzed and compared, so as to identify their respective distinguishing functions. The annotation of the SAGE libraries was performed with a B. mori reference tag collection, which was extracted from a novel set of Bombyx ESTs, sequenced from the 3' side. Most of the tags appeared at similar relative concentration within the two libraries, and corresponded with region-specific and highly abundant silk proteins. Strikingly,in addition to tags from silk protein mRNAs, 19 abundant tags were found (>/= 0.1%), in the median cell library, which were absent in the posterior cell tag collection. With the exception of tags from SP1 mRNA, no PSG specific tags were found in this subset class. The analysis of some of the MSG-specific transcripts, suggested that middle silk gland cells have diversified functions, in addition to their well characterized role in silk sericins synthesis and secretion.
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Outcome of children treated with haematopoietic-stem cell transplantations from donors expressing the rare C77G variant of the PTPRC (CD45) gene
- Journal : Br J Haematol
- 2011
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Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma.
- Journal : J Hepatol
- 2011
- BACKGROUND & AIMS: We previously reported the frequent overexpression of the FZD7 membrane receptor in hepatocellular carcinoma (HCC) and its role for controllingcancer phenotype. Herein, this study aimed at assessing the anticancer properties of compounds inhibiting FZD7 activity by disrupting its binding with the cytosolic Dishevelled (DVL) adaptator. METHODS: We have designed small interfering peptides (RHPDs) that are able to enter within cells and to competitively antagonize the binding of FZD7 to the PDZ domain of DVL. Their anti-neoplastic properties were assessed in vitro on a panel of human HCC cell lines and in vivo on the SV40-TAg transgenic mouse model of HCC. RESULTS: We have shown that RHPDs decrease cell viability via apoptosis depending on their affinity for PDZ, with a therapeutic index between cancerous and non-cancerous cells. RHPD properties were linked to beta-catenin degradation and PKCdelta activation. In transgenic mice, intra-tumor injection of RHPDs inhibited HCC progression. CONCLUSIONS: We have completed a proof-of-concept showing that in vitro and in vivo the pharmacological inhibition of FZD7 displays anti-cancerousproperties against HCC. The mechanisms can involve beta-catenin and PKCdelta modulations. Further studies are warranted to design protocols showing the compatibility with systemic in vivo applications.
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Real-time imaging of cotranscriptional splicing reveals a kinetic model that reduces noise: implications for alternative splicing regulation
- Journal : J Cell Biol
- 2011
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Telomere deregulations possess cytogenetic, phenotype, and prognostic specificities in acute leukemias
- Journal : Exp Hematol
- 2011
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The emerging role of pre-messenger RNA splicing in stress responses: sending alternative messages and silent messengers
- Journal : RNA Biol
- 2011
Link to PubMed entry