A fuzzy gene expression-based computational approach improves breast cancer prognostication

A fuzzy computational approach that takes into account several molecular subtypes in order to provide more accurate breast cancer prognosi

The Hsp90 chaperone controls the biogenesis of L7Ae RNPs through conserved machinery

RNA-binding proteins of the L7Ae family are at the heart of many essential ribonucleoproteins (RNPs), including box C/D and H/ACA small nucleolar RNPs, U4 small nuclear RNP, telomerase, and messenger RNPs coding for selenoproteins. In this study, we show that Nufip and its yeast homologue Rsa1 are key components of the machinery that assembles these RNPs. We observed that Rsa1 and Nufip bind several L7Ae proteins and tether them to other core proteins in the immature particles. Surprisingly, Rsa1 and Nufip also link assembling RNPs with the AAA + adenosine triphosphatases hRvb1 and hRvb2 and with the Hsp90 chaperone through two conserved adaptors, Tah1/hSpagh and Pih1. Inhibition of Hsp90 in human cells prevents the accumulation of U3, U4, and telomerase RNAs and decreases the levels of newly synthesized hNop58, hNHP2, 15.5K, and SBP2. Thus, Hsp90 may control the folding of these proteins during the formation of new RNPs. This suggests that Hsp90 functions as a master regulator of cell proliferation by allowing simultaneous control of cell signaling and cell growth

Regulation of DNA Methylation Patterns by CK2-Mediated Phosphorylation of Dnmt3a

DNA methylation is a central epigenetic modification that is established by de novo DNA methyltransferases. The mechanisms underlying the generation of genomic methylation patterns are still poorly understood. Using mass spectrometry and a phosphospecific Dnmt3a antibody, we demonstrate that CK2 phosphorylates endogenous Dnmt3a at two key residues located near its PWWP domain, thereby downregulating the ability of Dnmt3a to methylate DNA. Genome-wide DNA methylation analysis shows that CK2 primarily modulates CpG methylation of several repeats, most notably of Alu SINEs. This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. By revealing phosphorylation as a mode of regulation of de novo DNA methyltransferase function and by uncovering a mechanism for the regulation of methylation at repetitive elements, our results shed light on the origin of DNA methylation patterns

Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex

Molecular left-right (L-R) asymmetry is established at the node of the mouse embryo as a result of the sensing of a leftward fluid flow by immotile cilia of perinodal crown cells and the consequent degradation of Dand5 mRNA on the left side. We here examined how the fluid flow induces Dand5 mRNA decay. We found that the first 200 nucleotides in the 3′ untranslated region (3′-UTR) of Dand5 mRNA are necessary and sufficient for the left-sided decay and to mediate the response of a 3′-UTR reporter transgene to Ca2+, the cation channel Pkd2, the RNA-binding protein Bicc1 and their regulation by the flow direction. We show that Bicc1 preferentially recognizes GACR and YGAC sequences, which can explain the specific binding to a conserved GACGUGAC motif located in the proximal Dand5 3′-UTR. The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is also required for Dand5 mRNA decay at the node. These results suggest that Ca2+ currents induced by leftward fluid flow stimulate Bicc1 and Ccr4-Not to mediate Dand5 mRNA degradation specifically on the left side of the node

Global MicroRNA Expression Profiling Identifies MiR-210 Associated with Tumor Proliferation, Invasion and Poor Clinical Outcome in Breast Cancer

Aberrant microRNA (miRNA) expression is associated with cancer and has potential diagnostic and prognostic value in various malignancies. In this study, we investigated miRNA profiling as a complementary tool to improve our understanding of breast cancer (BC) biology and to assess whether miRNA expression could predict clinical outcome of BC patients.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Study of the biogenesis process of box C/D small nucleolar ribonucleoparticles (C/D snoRNPs) in the yeast Saccharomyces cerevisiae : functional and structural characterization of a machinery dedicated to assembly of these RNPs

Les protéines de la famille L7Ae sont les constituants de nombreuses RNP essentielles. Chez les vertébrés, les particules snoRNP C/D et H/ACA sont impliquées dans la biogenèse des ribosomes, la UsnRNP U4 dans l'épissage des pré-ARNm, le complexe télomérase dans la réplication des télomères, et les mRNP SECIS dans la traduction des sélénoprotéines. Comme c'est le cas pour la majorité des RNP eucaryotes, leur assemblage, sous forme d'entités fonctionnelles, ne constitue pas un processus autonome et requiert l'intervention de facteurs spécialisés. En basant notre étude sur l'assemblage des snoRNP C/D, dans l'organisme modèle Saccharomyces cerevisiae, et en utilisant des approches de biologie moléculaire, de biochimie et de génétique, nous avons entrepris de caractériser ces événements. Nos travaux ont contribué à identifier un ensemble de protéines, agissant de façon coordonnée au sein d'une machinerie conservée entre la levure et l'homme. Cette dernière est composée de deux principales sous-unités : (i) Rsa1p/NUFIP, une protéine plate-forme, qui interagit avec certaines protéines de la famille L7Ae et facilite l'assemblage des RNP, (ii) le complexe R2TP (Rvb1p/TIP49, Rvb2p/TIP48, Pih1p/PIH1, Tah1p/SPAGH), qui pourrait opérer des remodelages conformationnels nécessaires à la formation des RNP matures. En plus de ces acteurs centraux, d'autres facteurs sont apparus intimement liés à ce mécanisme. La protéine Hit1p/TRIP3, interagit notamment avec Rsa1p/NUFIP et s'est avéré requise pour assurer sa stabilité chez la levure. La chaperonne HSP90, dont le rôle est prédominant chez l'homme, exerce son activité sur certains constituants des RNP. Enfin, la protéine Bcd1p/BCD1 pourrait être associée à cette machinerie dans le cadre spécifique de l'assemblage des snoRNP C/DThe L7Ae family proteins are essential components of many RNPs. In vertebrates, C/D and H/ACA snoRNPs are involved in ribosome biogenesis, the U4 snRNP in pre-mRNA splicing, the telomerase complex in telomeres replication, and mRNP SECIS in selenoproteins translation. Like most eukaryotic RNPs, assembly in functional entities is not an autonomous process and requires the intervention of specialized factors. Basing our study on the assembly of C/D snoRNP in the model organism Saccharomyces cerevisiae, and using approaches of molecular biology, biochemistry and genetics, we undertook to decipher these mechanisms. Our work has helped to identify a set of proteins, acting in a coordinated manner within a machinery conserved between yeast and human. This machinery consists of two major subunits: (i) Rsa1p/NUFIP, a platform protein that interacts with some proteins of the L7Ae family and facilitates the RNPs assembly, (ii) the R2TP complex (Rvb1p/TIP49, Rvb2p/TIP48, Pih1p/PIH1, Tah1p/SPAGH), which could induce conformational remodeling necessary for the formation of mature RNPs. In addition to these key players, other factors appeared closely linked to this mechanism. The Hit1p/TRIP3 protein interacts with Rsa1p/NUFIP and is required to ensure its stability in yeast. HSP90 chaperone, whose role is predominant in human, operates on some components of the RNPs. Finally, the Bcd1p/BCD1 protein is associated specifically with this machinery during C/D snoRNPs assembl

Étude des processus de biogenèse des petites particules ribonucléoprotéiques nucléolaires à boîtes C/D (snoRNP C/D) chez la levure Saccharomyces cerevisiae : caractérisation fonctionnelle et structurale d'une machinerie dédiée à l'assemblage de ces RNP

Accès restreint aux membres de l'Université de Lorraine jusqu'au 2014-12-31The L7Ae family proteins are essential components of many RNPs. In vertebrates, C/D and H/ACA snoRNPs are involved in ribosome biogenesis, the U4 snRNP in pre-mRNA splicing, the telomerase complex in telomeres replication, and mRNP SECIS in selenoproteins translation. Like most eukaryotic RNPs, assembly in functional entities is not an autonomous process and requires the intervention of specialized factors. Basing our study on the assembly of C/D snoRNP in the model organism Saccharomyces cerevisiae, and using approaches of molecular biology, biochemistry and genetics, we undertook to decipher these mechanisms. Our work has helped to identify a set of proteins, acting in a coordinated manner within a machinery conserved between yeast and human. This machinery consists of two major subunits: (i) Rsa1p/NUFIP, a platform protein that interacts with some proteins of the L7Ae family and facilitates the RNPs assembly, (ii) the R2TP complex (Rvb1p/TIP49, Rvb2p/TIP48, Pih1p/PIH1, Tah1p/SPAGH), which could induce conformational remodeling necessary for the formation of mature RNPs. In addition to these key players, other factors appeared closely linked to this mechanism. The Hit1p/TRIP3 protein interacts with Rsa1p/NUFIP and is required to ensure its stability in yeast. HSP90 chaperone, whose role is predominant in human, operates on some components of the RNPs. Finally, the Bcd1p/BCD1 protein is associated specifically with this machinery during C/D snoRNPs assemblyLes protéines de la famille L7Ae sont les constituants de nombreuses RNP essentielles. Chez les vertébrés, les particules snoRNP C/D et H/ACA sont impliquées dans la biogenèse des ribosomes, la UsnRNP U4 dans l'épissage des pré-ARNm, le complexe télomérase dans la réplication des télomères, et les mRNP SECIS dans la traduction des sélénoprotéines. Comme c'est le cas pour la majorité des RNP eucaryotes, leur assemblage, sous forme d'entités fonctionnelles, ne constitue pas un processus autonome et requiert l'intervention de facteurs spécialisés. En basant notre étude sur l'assemblage des snoRNP C/D, dans l'organisme modèle Saccharomyces cerevisiae, et en utilisant des approches de biologie moléculaire, de biochimie et de génétique, nous avons entrepris de caractériser ces événements. Nos travaux ont contribué à identifier un ensemble de protéines, agissant de façon coordonnée au sein d'une machinerie conservée entre la levure et l'homme. Cette dernière est composée de deux principales sous-unités : (i) Rsa1p/NUFIP, une protéine plate-forme, qui interagit avec certaines protéines de la famille L7Ae et facilite l'assemblage des RNP, (ii) le complexe R2TP (Rvb1p/TIP49, Rvb2p/TIP48, Pih1p/PIH1, Tah1p/SPAGH), qui pourrait opérer des remodelages conformationnels nécessaires à la formation des RNP matures. En plus de ces acteurs centraux, d'autres facteurs sont apparus intimement liés à ce mécanisme. La protéine Hit1p/TRIP3, interagit notamment avec Rsa1p/NUFIP et s'est avéré requise pour assurer sa stabilité chez la levure. La chaperonne HSP90, dont le rôle est prédominant chez l'homme, exerce son activité sur certains constituants des RNP. Enfin, la protéine Bcd1p/BCD1 pourrait être associée à cette machinerie dans le cadre spécifique de l'assemblage des snoRNP C/

miR210: a potential biomarker for predicting clinical outcome in breast cancer

AACR Meeting Abstracts online - April 2008 - Abstract 929info:eu-repo/semantics/nonPublishe